Peter J. O’Dwyer and A. Hilary Calvert
INTRODUCTION
The platinum drugs represent a unique and important class of antitumor compounds. Alone or in combination with other chemotherapeutic agents, cis-diamminedichloroplatinum (II) (cisplatin) and its analogs have made a significant impact on the treatment of a variety of solid tumors for nearly 40 years. The unique activity and toxicity profile observed with cisplatin in early clinical trials fueled the development of platinum analogs that are less toxic and more active against a variety of tumor types, including those that have developed resistance to cisplatin. In addition to cisplatin, two other platinum complexes are currently approved for use in the United States: cis-diamminecyclobutanedicarboxylate platinum (II) (carboplatin) and 1,2-diaminocyclohexaneoxalato platinum (II) (oxaliplatin). Several other analogs with unique activities are in various stages of clinical development, and nedaplatin (Japan) and lobaplatin (China) are locally registered. Progress in the development of superior analogs requires a thorough understanding of the chemical, biologic, pharmacokinetic, and pharmacodynamic properties of this important class of drugs.
HISTORY
The realization that platinum complexes exhibited antitumor activity began serendipitously in a series of experiments to investigate the effect of electromagnetic radiation on the growth of bacteria, carried out by Dr. Barnett Rosenberg and colleagues beginning in 1961.1,2 Exposure of the bacteria to an electric field resulted in a profound change in their morphology; this effect was found not to be from the electric field, but from electrolysis products produced by the platinum electrodes. An analysis of these products resulted in the identification of the cis-isomer of a platinum coordination complex as the active compound. Tests of cis-diamminedichloroplatinum (II) in mice bearing several model tumor types indicated that cisplatin exhibited a broad spectrum of antitumor activity. Although early clinical trials demonstrated responses in several tumor types, particularly testicular cancers, the severe renal and gastrointestinal toxicity caused by the drug nearly led to its abandonment. Work at Memorial Sloan-Kettering3,4 showed that these effects could be ameliorated, in part, by aggressive prehydration, which rekindled interest in its clinical use. Currently, cisplatin is curative in testicular cancer and significantly prolongs survival in combination regimens for ovarian, lung, head and neck, bladder, and upper gastrointestinal (GI) cancers. Its role is being reexamined in other tumors, too, and especially breast cancer.
PLATINUM CHEMISTRY
Platinum exists primarily in either a 2+ or 4+ oxidation state. These oxidation states dictate the stereochemistry of the ligands surrounding the platinum atom. Platinum (II) compounds exhibit a square planar geometry, in which the ammine ligands (also called carrier groups) are relatively stable, whereas the opposite, more polar ligands (leaving groups) are more easily displaced and so confer reactivity toward charged macromolecules, including DNA.5 The stereochemistry of platinum complexes is critical to their antitumor activity as evidenced by the significantly reduced efficacy observed with trans-diamminedichloroplatinum (II).
In an aqueous solution, the chloride leaving groups of cisplatin are subject to mono- and diaqua substitution, particularly at chloride concentrations below 100 mmol, which characterize the intracellular environment. The administration of cisplatin in high chloride solutions (normal saline usually), therefore, contributes to stability. Intracellular formation of partially and fully aquated complexes creates the chloroaqua and hydroxoaqua cisplatin species that bind DNA.6
PLATINUM COMPLEXES AFTER CISPLATIN
Early in the clinical development of cisplatin, it became clear that its toxicity was a limitation to its therapeutic effectiveness, and that its activity, although striking in certain diseases, did not extend to all cancers. These observations then motivated a search for structural analogs with less toxicity and a different profile of antitumor activity. In addition, the side effects of cisplatin stimulated the development of antiemetics and other supportive care measures for use with chemotherapy. Progress in understanding the chemistry and pharmacokinetics of cisplatin has guided the development of new analogs. In general, modification of the chloride leaving groups of cisplatin results in compounds with different pharmacokinetics and reactivity towards DNA, whereas modification of the carrier ligands alters the activity of the resulting complex. The features of the more important platinum analogs that have been developed are shown in Figure 18.1.
Carboplatin
The carboplatin molecule has the same ammine carrier ligands as cisplatin. Using a murine screen for nephrotoxicity, Harrap and Calvert discovered that substituting a cyclobutanedicarboxylate moiety for the two chloride ligands of cisplatin resulted in a complex with reduced renal toxicity. This observation was translated to the clinic in the form of carboplatin, a more stable and pharmacokinetically predictable analog.7,8 The results in humans were accurately predicted by the animal models, and marrow toxicity rather than nephrotoxicity was the principal side effect. At effective doses, carboplatin produced less nausea, vomiting, nephrotoxicity, and neurotoxicity than cisplatin. Furthermore, the myelosuppression was closely associated with the pharmacokinetics. The work of Calvert et al.9 and Egorin and colleagues10 showed that toxicity can be made more predictable and dose intensity less variable by dosing strategies based on the exposure. Carboplatin was shown to be indistinguishable from cisplatin in its clinical activity in all but a handful of tumor types and is the most frequently used form of platinum in current use. Cisplatin and carboplatin have almost superimposable profiles of activity in the NCI60 cell line screen, which further emphasizes the dependence of spectrum of activity on the carrier ligand.
Oxaliplatin
Compounds with activity in cisplatin-resistant models emerged from modifications to the carrier group (see left side of the analogs in Fig. 18.1). Connors, in the late 1960s, synthesized platinum coordination compounds with varying physicochemical characteristics and found that the series that possessed a diaminocyclohexane (DACH) carrier group was active in models of cancer in vitro11 and in vivo.12Subsequent studies supported the idea that DACH-based platinum complexes were non–cross-resistant with cisplatin, and DACH derivatives exhibited a unique cytotoxicity profile compared to cisplatin and carboplatin in the National Cancer Institute 60 cell line screen.13–15 After a number of delays, a DACH analog that had been synthesized by Kidani and colleagues in the early 1970s, was developed in the clinic.13 Oxaliplatin, a coordination compound of a DACH carrier group and an oxalato leaving group, was active in cisplatin-resistant tumor models. Like cisplatin, oxaliplatin preferentially forms adducts at the N7 position of guanine and, to a lesser extent, adenine. However, there is evidence that the three-dimensional structure of the DNA adducts and biologic response(s) they elicit are different from those of cisplatin. Oxaliplatin demonstrated activity in combination with 5-fluorouracil and leucovorin in colon cancer, a disease that is unresponsive to cisplatin. This finding validated the focus on cisplatin-resistant preclinical models to identify new active molecules. Oxaliplatin is approved for the treatment of advanced colorectal cancer, and enhances cure rates in the adjuvant setting. The therapeutic role of oxaliplatin has been found to extend to pancreatic, gastric, and esophageal cancers, in all of which it is the more active platinum derivative.
Nedaplatin and Lobaplatin
Nedaplatin is cis-diammineglycolatoplatinum, developed as a less nephrotoxic second-generation platinum analog, has been shown to be active in a range of tumors similar to that of cisplatin and carboplatin.16 As a diammine structure, nedaplatin would fall among the cisplatin analogs analyzed in the NCI60 cell line screen,17 and this activity is therefore anticipated. Lobaplatin is a platinum (II) complex in which the leaving group is lactic acid and the stable ammine ligand is 1,2-bis(aminomethyl)cyclobutane. In a similar way to oxaliplatin the stable ammine ligand may convey some non–cross-resistance compared to cisplatin or carboplatin. It is licensed in China for the breast cancer, small-cell lung cancer, and chronic myelogenous leukemia. It is unique among the platinum drugs for its approval for breast cancer, but there are few published clinical data and no randomized trials. It has not achieved approval in the United States or Europe.
Newer Platinum Structures
The octahedral stereochemistry adopted by platinum (IV) compounds has led investigators to speculate that they may exhibit a different spectrum of activity than that of platinum (II) drugs. Two compounds that were tested clinically without much success are ormaplatin and iproplatin. Two other platinum (IV) compounds that exhibit novel structural features, satraplatin (previously JM216) and JM335 (trans-ammine[cyclohexylamine]dichlorodihydroxo platinum [IV]), underwent more limited development. Satraplatin was the first orally active platinum compound, and showed some activity in lung and ovarian cancers, but despite promising activity in prostate cancer, a phase III trial was not successful.18,19
An approach based on the chemistry of the platinum-DNA interaction led to design and synthesis by Farrell et al.20 of a novel class of compounds containing multiple platinum atoms (see Fig. 18.1). These bi- and trinuclear structures form adducts that span greater distances across the minor groove of DNA and have a profile of cell kill that differs from that of the small molecules. These compounds are unique in that their interaction with DNA is considerably different from that of cisplatin, particularly in the abundance of interstrand cross-links formed. Clinical development of candidate compounds is at a preliminary stage.
Efforts have been made to design novel platinum analogs that can circumvent putative cisplatin resistance mechanisms. An example is cis-amminedichloro(2-methylpyridine) platinum (II) (also known as AMD473 and ZD0473). This compound is a sterically hindered platinum complex that was designed to have minimal reactivity with thiols and thus avoid inactivation by molecules such as glutathione.21,22Responses were identified with its use in the clinic, but development was curtailed based on low levels of activity. The recent description of a monofunctional platinum (II) analog, phenanthriplatin, from the lab of Lippard is potentially of great interest, based on both potency in vitro and a mechanistic profile different from existing analogs.23 A renewed appreciation that chemotherapeutic drugs have a continuing role in managing cancer is likely to prompt additional clinical development of novel platinum structures.
MECHANISM OF ACTION
DNA Adduct Formation
DNA has long been thought to be the major therapeutic target for platinum compounds. The cytotoxic effects are determined, in part, by the structure and relative amount of DNA adducts formed. Cisplatin and its analogs react preferentially at the N7 position of guanine and adenine residues to form a variety of monofunctional and bifunctional adducts.24 The monoadducts may form intrastrand or interstrand cross-links. The predominant lesions that are formed when platinum compounds bind DNA are d(GpG)Pt intrastrand cross-links. Cisplatin also forms interstrand cross-links between guanine residues located on opposite strands, and these account for less than 5% of the total DNA-bound platinum. The formation of adducts and cross-links has been associated with therapeutic efficacy.25,26 These adducts may contribute to the drug’s cytotoxicity because they impede certain cellular processes that require the separation of both DNA strands, such as replication and transcription. The adducts formed in the reaction between carboplatin and DNA in cultured cells are essentially the same as those of cisplatin; however, higher concentrations of carboplatin are required (20- to 40-fold for cells) to obtain equivalent total platinum-DNA adduct levels due to its slower rate of aquation.27 Oxaliplatin intrastrand adducts form even more slowly due to a slower rate of conversion from monoadducts; however, they are formed at similar DNA sequences and regions as cisplatin adducts. At equitoxic doses, oxaliplatin forms fewer DNA adducts than does cisplatin. This has been interpreted to mean that oxaliplatin lesions are more cytotoxic than those formed by cisplatin.
The differences observed in cytotoxicity between the diammine (e.g., cisplatin, carboplatin) and DACH platinum compounds may not depend on the type and relative amounts of the adducts formed, but on the overall three-dimensional structure of the adduct and its recognition by various cellular proteins. The major difference between them is the protrusion of the DACH moiety of oxaliplatin into the major groove of DNA, which thus produces a bulkier adduct than that of cisplatin. This bulkier, more hydrophobic adduct seems to be recognized differently by cellular proteins involved in sensing DNA damage.28The functional consequences are twofold: Proteins such as polymerases that recognize and participate in reactions on DNA under normal circumstances may be perturbed, whereas processes that are controlled by proteins that recognize damaged DNA may become activated (the DNA damage response). The latter group of proteins function both in the DNA repair process and in cellular signaling toward cell survival/death decisions.
DNA Interstrand Cross-Links
Although the DNA adducts are well-recognized to result in G-G interstrand cross-links, like classical alkylating agents, platinum drugs have the capacity to form intrastrand cross-links, albeit to a lesser degree. By blocking essential aspects of DNA metabolism, such as replication and transcription, intrastrand cross-links are highly cytotoxic. Recent studies have drawn attention both to the cytotoxicity of these lesions, and their differing mechanisms of repair, both replication dependent and independent.29,30 These studies may have clinical implications in selecting patients for therapy based on the repair competence of tumors.
CELLULAR RESPONSES TO PLATINUM-INDUCED DNA DAMAGE
Multiple cellular outcomes may follow the formation of platinum-DNA adducts, including cell death by apoptosis, necrosis, or mitotic catastrophe, or cell survival by activation of various protective mechanisms including DNA repair, DNA damage signaling pathways, cell cycle arrest, and autophagy (the last may have a dual role, possibly context dependent).
Cell Fate
The cellular effects following DNA binding by platinum drugs have been analyzed. The studies of Sorenson and Eastman,31 using DNA repair-deficient Chinese hamster ovary (CHO) cells, indicated that passage through the S phase is necessary for G2 arrest and cell death, which suggests that DNA replication on a damaged template may result in the accumulation of further damage. An aberrant mitosis was observed before apoptosis in this model.
DNA Damage Recognition
Among the initiation events that ultimately result in platinum drug–induced cell death are the binding of platinum-DNA damage recognition proteins, which then seed the accumulation of a large protein complex capable both of DNA damage signaling (as to cell cycle proteins to halt replication) and repair of the damaged DNA. Among the DNA-binding proteins are the high-mobility group proteins HMG1 and HMG2.32–34 These proteins are capable of bending DNA as well as recognizing bent DNA structures, such as that produced by cisplatin, and different specificities for cisplatin and for oxaliplatin adducts are observed in structural studies.35,36 Other candidate platinum-DNA damage recognition proteins include histone H1, RNA polymerase I transcription upstream binding factor (hUBF), the TATA binding protein (TBP), and proteins involved in mismatch repair (MMR). The MMR complex has been implicated in cisplatin sensitivity.37 Studies have shown that the MSH2 and MLH1 proteins participate in the recognition of DNA adducts formed by cisplatin, but not oxaliplatin, which could contribute to differences in the cytotoxicity profiles observed between these two platinum complexes.
DNA Damage Signaling
A number of signaling events have been shown to occur after treatment of cells with platinum drugs.38 For example, the ATM- and Rad3-related (ATR) proteins that are involved in cell-cycle checkpoint activation are activated by cisplatin. These kinases phosphorylate and activate several downstream effectors that regulate cell cycle, DNA repair, cell survival, and apoptosis, including p53, CHK2, and members of the mitogen-activated protein kinase (MAPK) pathway (extracellular signal-related kinase [ERK], c-Jun amino-terminal kinase [JNK], and p38 kinase). Recent data especially implicate signaling through the JNK pathway, and inhibition at the level of JNK seems especially relevant to platinum drug cytotoxicity in vitro and in vivo.39,40 The pleiotropic nature of this stress response only grows, because each of these molecules subsequently controls the activity and expression of many more proteins. As a result of this complexity, acting in the context of variable genomic tumor aberrations, therapeutic strategies directed to these pathways have been slow to emerge. However, clinical trials to investigate specific inhibitors of DNA damage responses are underway and hold promise. It is also relevant to point out that these signaling pathways affect not just the tumor cell, but also may communicate to cells in the microenvironment, the responses of which may also determine the effectiveness of therapy.
IS DNA THE ONLY TARGET?
Early analyses of the action of cytotoxic drugs included a probe of whether effects on DNA were sufficient to explain drug effects. A pioneer in this field was Tritton,41 who proposed that effects of DNA-intercalating agents on the plasma membrane could underlie the cytotoxicity of the drug. More recently, enucleated cells were shown to be susceptible to cisplatin, and a seminal paper from Voest and colleagues showed that platinum sensitivity was determined not solely by the accumulation of DNA damage in the tumor cell.42 In analyzing the contribution of cells in the microenvironment of tumors, he showed that tumor infiltration with mesenchymal stem cells could confer drug resistance. A search for secreted factors defined platinum-induced fatty acids, metabolic products in the thromboxane synthetase, and cyclooxygenase-1 pathways as determining the effectiveness of drug therapy. A proteomic study in cisplatin-sensitive and resistant cells confirmed the substantial effects of drug exposure on lipid metabolites and their relation to susceptibility. A current focus on therapies directed to the microenvironment, including immunologic and anti-inflammatory interventions,43 has the potential to expand our ability to apply platinum drugs in the clinic.
MECHANISMS OF RESISTANCE
The major limitation to the successful treatment of solid tumors with platinum-based chemotherapy is the emergence of drug-resistant tumor cells.44 Developments in tumor biology have advanced our thinking with regard to how and when these cells emerge; heterogeneity within a tumor even at its earliest diagnosis reflects the emergence of treatment-resistant clones even in advance of selection pressure and the realization that resistance may not be specific to the DNA-damaging drug. Indeed, this may be reflected clinically in the finding that after progression on initial chemotherapy, the use of second-line therapy is usually associated with a shorter duration of response.
Currently described mechanisms of platinum drug resistance (Fig. 18.2) include reduced cellular accumulation, intracellular detoxification, repair of Pt-DNA lesions, increased damage tolerance, and the activation of cellular defense mechanisms such as autophagy. In addition, we have already alluded to exogenous influences on mechanism, as may be mediated by other cells, metabolites, of physicochemical conditions (such as hypoxia) in the tumor microenvironment. It must be acknowledged, however, that our insights are very limited as to why some tumors respond and others do not to platinum chemotherapy. As genome sequencing yields increasing and often surprising revelations about the genes that drive cancers and the complexity inherent in cancers of a single histologic type, it is likely that when associated with outcomes in large patient populations, patterns will emerge to guide selection of therapies.
Reduced Accumulation
Platinum uptake in cells occurs by simple diffusion and by carrier-mediated mechanisms. Inhibition of transport mechanisms has a marked effect on intracellular platinum accumulation, and Howell’s group has shown the importance of the copper transporters CTR-1 and CTR-2 in regulating the influx of various platinum analogs in eukaryotic cells.45,46 The contribution of these mechanisms to clinical platinum drug resistance is being explored.47 Accumulation may also be influenced by enhanced efflux, and various transport proteins are upregulated in cell lines selected for acquired resistance, and in platinum-resistant ovarian cancers.
Inactivation
Platinum complexes are highly reactive molecules and bind rapidly to multiple cellular macromolecules. Protection from such chemicals in the environment is afforded by cellular thiols, including small peptides such as glutathione (GSH) and larger proteins as exemplified by metallothionein (MT). There are many reports of an association between platinum drug sensitivity and glutathione levels48–50; however, reducing intracellular glutathione levels with drugs such as buthionine sulfoximine has resulted in only low to modest potentiation of cisplatin sensitivity.51 Buthionine sulfoximine was developed for clinical use, and some impact on GSH content of tumors and normal tissues was demonstrated. However, the depletion of GSH was not consistent, and ultimately, the cost of producing the active stereoisomer of the drug was judged prohibitive. Inactivation of the platinum drugs may also occur through binding to the MTs, a family of sulfhydryl-rich, low–molecular-weight proteins that participate in heavy metal binding and detoxification; however, the contribution of MT to clinical platinum drug resistance is unclear, and a therapeutic role has not emerged.
Increased DNA Repair
Once platinum-DNA adducts are formed, cells must either repair or tolerate the damage to survive. In general, the capacity to repair DNA damage seems to play a role in determining a tumor cell’s sensitivity to platinum drugs and other DNA-damaging agents. For example, tumors that are unusually sensitive to cisplatin, such as testicular nonseminomatous germ cell tumors, may be deficient in their ability to repair platinum-DNA adducts.52 The increased repair of platinum-DNA lesions in cisplatin-resistant cell lines as compared to their sensitive counterparts has been shown in several human cancer cell lines, but translation of these observations to the clinic has been difficult. The repair of platinum-DNA adducts appears to occur predominantly by nucleotide excision repair (NER), with a role for MMR under certain circumstances.53 The molecular basis for the increased repair activity observed in cisplatin-resistant cells is not known precisely, but formation of the ERCC1/XPF protein complex may be a key step. Selvakumaran et al.54 showed that the downregulation of ERCC-1 using an antisense approach sensitized a platinum-resistant cell line to cisplatin both in vitro and in vivo. There is substantial clinical evidence that implicates ERCC1 expression in increased NER and cisplatin resistance, and high expression of ERCC1 has been demonstrated to confer a worse outcome after cisplatin treatment in several resistant tumors. The most extensive study of this as a marker has been in non–small-cell lung cancer, results in which were summarized and analyzed by Hubner et al.55 In gastric cancer also, high levels of ERCC1 are associated with resistance to cisplatin treatment.56–58 However, a recent reevaluation of discrepant results questioned the reliability of the assays of ERCC1 and their relationship to function.59 These data suggest that there is a relationship between ERCC1 expression and treatment, but that the lag in marker development precludes implementation of a predictive assay until additional studies have been performed.
Perhaps the most striking evidence that DNA repair is a determinant of platinum drug responses is that breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers are particularly responsive to cisplatin or carboplatin. These cancers are also sensitive to inhibitors of poly(ADP-ribose)polymerase (PARPi), several of which are currently in clinical development. The mechanism of the sensitivity to PARPi has been elucidated. Both the BRCA1 and 2 proteins for part of the homologous recombination repair (HR) system that achieves error-free repair of double strand breaks. Carriers are heterozygous and, therefore, have normal repair function, but loss of the second allele leads to the use of error-prone backup systems and is therefore oncogenic. The cancers that arise are unable to perform HR and, therefore, are sensitive to drugs that induce single strand breaks, such as PARPi.60,61 A mechanism of resistance to PARPi has been described, which is due to reactivation of the function of the BRCA2 leading to restoration of HR and sensitivity to PARPi.62 This reactivation is accomplished by an intragenic deletion and the restoration of an open reading frame. It has further been shown that such revertant cells are resistant to cisplatin as well as PARPi. Finally, recurrent cancers in BRCA2 mutation carriers, which have acquired platinum resistance, have been shown to have undergone reversion of the BRCA2 mutation.63 This clearly shows that the HR system can be one cause of cisplatin resistance. However, not all cisplatin-resistant patients are also resistant to PARPi,64 showing that there are multiple other causes of cis/carboplatin resistance.
Combinations of platinum drugs with PARPi are being actively pursued in patients with BRCA-related tumors and also in patients whose tumors are likely to have acquired loss of HR function (poorly differentiated serous ovarian cancer and triple negative breast cancer).
Autophagy
After platinum-DNA adduct formation, the cell detects the DNA damage and initiates signaling through multiple pathways, the effects of which include mobilization of repair proteins; arrest of the cell cycle; altered transcriptional programs; redirection of energy production and consumption; activation of cell death pathways and, simultaneously, of pathways that would counter a cell death decision, and so to permit survival. A process recently characterized to perform the last function is autophagy. Initially described as a mechanism of cell death, autophagy represents a regulated dissolution of cellular elements into a characteristic set of subcellular organelles detectable by electron microscopy and linked by a particular profile of gene expression changes.65 Multiple stimuli precipitate these changes and have in common scarcity of nutrients that are required for survival, from oxygen and glucose withdrawal to less specific calorie deprivation, and inhibition of metabolic pathways. Autophagy is also a consequence of cytotoxic drug treatment and, more recently, has been appreciated as a means by which cells might survive the stress of cellular insults, and so become resistant to treatment.66 Amaravadi and colleagues67demonstrated that autophagy reversal can sensitize tumors to cytotoxic drugs and several trials of platinum compounds along with the autophagy inhibitor hydroxychloroquine are in progress.
Increased DNA Damage Tolerance
The net result of DNA damage signaling in a sensitive tumor cell is engagement of cell death pathways, including apoptosis, and therapeutic benefit. In a resistant tumor cell, the cell survives as a consequence of one or many of these mechanisms, and this can result in platinum-DNA damage tolerance or multidrug resistance phenotype, or both. Contributors to the tolerance might include deficient DNA MMR (which could excise the adduct if NER failed), enhanced replicative bypass (which essentially ignores the adduct, allowing the cell to survive, but could contribute to the increase in mutation frequency observed in chemotherapy-treated cancers), and altered signaling through stress-related kinases such as JNK, which can both alter transcriptional programs and activate autophagy. Indeed JNK, by phosphorylating Bcl-2 or Bcl-XL, and releasing beclin-1 from inhibition, acts as a key switch to turn on autophagy. The enhanced DNA damage tolerance, in addition to permitting persistence of the cancer cell, may have an additional deleterious effect by fostering further mutagenesis within the tumor, facilitating its evolution to a more malignant phenotype.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetic differences observed between platinum drugs may be attributed to the structure of their leaving groups. Platinum complexes containing leaving groups that are less easily displaced exhibit reduced plasma protein binding, longer plasma half-lives, and higher rates of renal clearance. These features are evident in the pharmacokinetic properties of cisplatin, carboplatin, and oxaliplatin, which are summarized in Table 18.1. Platinum drug pharmacokinetics have been reviewed.68
Cisplatin
After intravenous infusion, cisplatin rapidly diffuses into tissues and is covalently bound to plasma protein. More than 90% of platinum is bound to plasma protein at 4 hours after infusion. The disappearance of ultrafilterable platinum is rapid and occurs in a biphasic fashion. Half-lives of 10 to 30 minutes and 0.7 to 0.8 hours have been reported for the initial and terminal phases, respectively. Cisplatin excretion is dependent on renal function, which accounts for the majority of its elimination. The percentage of platinum excreted in the urine has been reported to be between 23% and 40% at 24 hours after infusion. Only a small percentage of the total platinum is excreted in the bile.
Carboplatin
The differences in pharmacokinetics observed between cisplatin and carboplatin depend primarily on the slower rate of conversion of carboplatin to a reactive species. Thus, the stability of carboplatin results in a low incidence of nephrotoxicity. Carboplatin diffuses rapidly into tissues after infusion; however, it is considerably more stable in plasma. Only 24% of a dose was bound to plasma protein at 4 hours after infusion. The disappearance of platinum from plasma after short intravenous infusions of carboplatin has been reported to occur in a biphasic or triphasic manner. The initial half-lives for total platinum, which vary considerably among several studies, are listed in Table 18.1. The half-lives for total platinum range from 12 to 98 minutes during the first phase (T1/2α) and from 1.3 to 1.7 hours during the second phase (T1/2β). Half-lives reported for the terminal phase range from 8.2 to 40 hours. The disappearance of ultrafilterable platinum is biphasic with T1/2α and T1/2β values ranging from 7.6 to 87 minutes and 1.7 to 5.9 hours, respectively. Carboplatin is excreted predominantly by the kidneys, and cumulative urinary excretion of platinum is 54% to 82%, most as unmodified carboplatin. The renal clearance of carboplatin is closely correlated with the glomerular filtration rate (GFR).69 This observation enabled Calvert et al.9 to design a carboplatin-dosing formula based on the individual patient’s GFR.
Oxaliplatin
After oxaliplatin infusion, platinum accumulates into three compartments: plasma-bound platinum, ultrafilterable platinum, and platinum associated with erythrocytes. When specific and sensitive mass spectrometric techniques are used, oxaliplatin itself is undetectable in plasma, even at end infusion.70 The active forms of the drug have not been extensively characterized. Approximately 85% of the total platinum is bound to plasma protein at 2 to 5 hours after infusion.71 Plasma elimination of total platinum and ultrafilterates is biphasic. The half-lives for the initial and terminal phases are 26 minutes and 38.7 hours, respectively, for total platinum and 21 minutes and 24.2 hours, respectively, for ultrafilterable platinum (see Table 18.1).72 Thus, as with carboplatin, substantial differences between total and free platinum kinetics are not observed. As with cisplatin, a prolonged retention of oxaliplatin is observed in red blood cells. However, unlike cisplatin, oxaliplatin does not accumulate to any significant level after multiple courses of treatment.71 This may explain why neurotoxicity associated with oxaliplatin is reversible. Oxaliplatin is eliminated predominantly by the kidneys, with more than 50% of the platinum being excreted in the urine at 48 hours.
Pharmacodynamics
Pharmacodynamics relates pharmacokinetic indices of drug exposure to biologic measures of drug effect, usually toxicity to normal tissues or tumor cell kill. Two issues to be addressed in such studies are whether the effectiveness of the drug can be enhanced and whether the toxicity can be attenuated by knowledge of the platinum pharmacokinetics in an individual. These questions are appropriate to the use of cytotoxic agents with relatively narrow therapeutic indices. Toxicity to normal tissues can be quantitated as a continuous variable when the drug causes myelosuppression. Thus, the early studies of carboplatin demonstrated a close relationship of changes in platelet counts to the area under the concentration-time curve (AUC) in the individual. The AUC was itself closely related to renal function, which was determined as creatinine clearance. Based on these observations, Egorin et al.,10 Calvert et al.,9 and Chatelut and colleagues73 derived formulas based on creatinine clearance to predict either the percentage change in platelet count or a target AUC. Application of pharmacodynamically guided dosing algorithms for carboplatin has been widely adopted as a means of avoiding overdosage (by producing acceptable nadir platelet counts) and of maximizing dose intensity in the individual. There is good evidence that this approach can decrease the risk of unacceptable toxicity. Accordingly, a dosing strategy based on renal function is recommended for the use of carboplatin.
A key question is whether maximizing carboplatin exposure in an individual can measurably increase the probability of tumor regression or survival. In an analysis by Jodrell et al.,74 carboplatin AUC was a predictor of response, thrombocytopenia, and leukopenia. The likelihood of a tumor response increased with increasing AUC up to a level of 5 to 7 mg × hour per milliliter, after which a plateau was reached. Similar results were obtained with carboplatin in combination with cyclophosphamide, and neither response rate nor survival was determined by the carboplatin AUC in a cohort of ovarian cancer patients.75As a result, most carboplatin recommended doses are based on an AUC in this range (for every 3 to 4 week schedules), and modifications of these are used for more frequent administration (as in combined chemoradiotherapy regimens).
The relationship of pharmacokinetics to response has been sought by investigating the cellular pharmacology of these agents.76 The formation and repair of the platinum-DNA adducts in human cells are not easily measured. Schellens and colleagues77,78 analyzed the pharmacokinetic and pharmacodynamic interactions of cisplatin administered as a single agent. In a series of patients with head and neck cancer, they found that cisplatin exposure (measured as the AUC) closely correlated with both the peak DNA adduct content in leukocytes and the area under the DNA-adduct time curve. These measures were important predictors of response, both individually and in logistic regression analysis. However, as an approach to determine who should or should not be treated with platinum drugs, it seems more likely that genomic analyses will provide guidance in the near future.
Pharmacogenomics
Variability in pharmacokinetics and pharmacodynamics of cytotoxic drugs is an important determinant of therapeutic index. This interindividual variation may be attributed in part to genetic differences among patients. Targeted analyses of germ-line DNA and, increasingly, Genome-wide association studies (GWAS) approaches, have yielded genotypic features associated with results of therapy. Detoxification pathways and DNA repair have emerged as having markers attributable to response of lack of it in response to platinum drugs. Single nucleotide polymorphisms (SNP) in genes related to glutathione metabolism and in several DNA repair genes have been identified in lung cancer, breast cancer, and various GI cancers. A concern is that larger trials have not always confirmed early findings. As yet, informative SNPs that could be used to define therapeutic strategies for individual patients have not yet been defined.
FORMULATION AND ADMINISTRATION
Cisplatin (Platinol)
Cisplatin is administered in a chloride-containing solution intravenously over 0.5 to 2.0 hours. To minimize the risk of nephrotoxicity, patients are prehydrated with at least 500 mL of salt-containing fluid. Immediately before cisplatin administration, mannitol (12.5 to 25.0 g) is given parenterally to maximize urine flow. A diuretic such as furosemide may be used also, along with parenteral antiemetics. These currently include dexamethasone together with a 5-hydroxytryptamine (5-HT3) antagonist. A minimum of 1 L of posthydration fluid is usually given. The intensity of hydration varies somewhat with the dose of cisplatin. High-dose cisplatin (up to 200 mg/m2 per course) may be administered in a formulation containing 3% sodium chloride, but this method is no longer widely used. Cisplatin may also be administered regionally to increase local drug exposure and diminish side effects. Its intraperitoneal use was defined by Ozols et al.79 and by Howell and colleagues.80 Measured drug exposure in the peritoneal cavity is some 50-fold higher compared to levels achieved with intravenous administration. At standard dosages in ovarian cancer patients with low-volume disease, a randomized intergroup trial suggested that intraperitoneal administration is superior to intravenous cisplatin in combination with intravenous cyclophosphamide.81 The development of combinations of carboplatin and paclitaxel has, however, superseded this technique in the treatment of ovarian cancer, and the intraperitoneal route is now infrequently used. Regional uses also include intra-arterial delivery (as for hepatic tumors, melanoma, and glioblastoma), but none have been adopted as a standard method of treatment. There is growing interest in chemoembolization for the treatment of tumors confined to the liver, and cisplatin is a component of many popular regimens.82
Carboplatin (Paraplatin)
Cisplatin treatment over 3 to 6 hours is burdensome for clinical resources and tiring for cancer patients. Previously given as an in-hospital treatment, it is now usually administered in the outpatient setting. The exigencies of the modern health-care environment have contributed to the expanding use of carboplatin as an alternative to cisplatin except in circumstances in which cisplatin is clearly the superior agent. Carboplatin is substantially easier to administer. Extensive hydration is not required because of the lack of nephrotoxicity at standard dosages. Carboplatin is reconstituted in chloride-free solutions (unlike cisplatin, because chloride can displace the leaving groups) and administered over 30 minutes as a rapid intravenous infusion.
Oxaliplatin (Eloxatin)
Oxaliplatin is also uncomplicated in its clinical administration. For bolus infusion, the required dose is administered in 500 mL of chloride-free diluent over a period of 2 hours. Oxaliplatin is most frequently given as a single dose every 2 weeks (85 mg/m2) or every 3 weeks (130 mg/m2), alone or with other active agents. It is common to pretreat patients with active antiemetics, such as a 5-HT3 antagonist, but the nausea is not as severe as with cisplatin. No prehydration is required. Besides a relatively low incidence of myelosuppression, the predominant toxicity of oxaliplatin is cumulative neurotoxicity. The development of an oropharyngeal dysesthesia, often precipitated by exposure to cold, may require prolonging the duration of administration to 6 hours. On occasion, the occurrence of hypersensitivity also requires slowing the infusion.
TOXICITY
A substantial body of literature documents the side effects of platinum compounds. As noted in the section titled History, earlier in this chapter, the toxicity of cisplatin was a driving force both in the search for less toxic analogs and for more effective treatments for its side effects, especially nausea and vomiting. The toxicities associated with cisplatin, carboplatin, and oxaliplatin are described in detail in the following sections and summarized in Table 18.2. Please review the package inserts for these drugs for full prescribing information and delineation of toxic effects.
Cisplatin
The side effects associated with cisplatin (at single doses of more than 50 mg/m2) include nausea and vomiting, nephrotoxicity, ototoxicity, neuropathy, and myelosuppression. Rare effects include visual impairment, seizures, arrhythmias, acute ischemic vascular events, glucose intolerance, and pancreatitis. The nausea and vomiting stimulated a search for new antiemetics. These effects are currently best managed with 5-HT3 antagonists, usually given with a glucocorticoid, although other combinations of agents are still widely used. In the weeks after treatment, continuous antiemetic therapy may be required. Nephrotoxicity is ameliorated but not completely prevented by hydration. The renal damage to both glomeruli and tubules is cumulative, and after cisplatin treatment, serum creatinine levels are no longer a reliable guide to GFR. An acute elevation of serum creatinine level may follow a cisplatin dose, but this index returns to normal with time. Tubule damage may be reflected in a salt-losing syndrome that also resolves with time.
Ototoxicity is a cumulative and irreversible side effect of cisplatin treatment that results from damage to the inner ear. The initial audiographic manifestation is loss of high-frequency acuity (4,000 to 8,000 Hz). When acuity is affected in the range of speech, cisplatin should be discontinued under most circumstances and carboplatin substituted where appropriate. Peripheral neuropathy is also cumulative, although less common than with agents such as vinca alkaloids. This neuropathy is usually reversible, although recovery is often slow. A number of agents with the potential for protection from neuropathy have been developed, but none is yet used widely.
Carboplatin
Myelosuppression, which is not usually severe with cisplatin, is the dose-limiting toxicity of carboplatin. The drug is most toxic to the platelet precursors, but neutropenia and anemia are frequently observed. The lowest platelet counts after a single dose of carboplatin are observed 17 to 21 days later, and recovery usually occurs by day 28. The effect is dose dependent, but individuals vary widely in their susceptibility. As shown by Egorin et al.10 and Calvert et al.,9 the severity of platelet toxicity is best accounted for by a measure of the drug exposure in an individual, the AUC. Both groups derived pharmacologically based formulas to predict toxicity and guide carboplatin dosing. That of Calvert and colleagues targets a particular exposure to carboplatin:
Dose (mg) = target AUC (mg • min/mL) × (GFR mL/min + 25)
This formula has been widely used to individualize carboplatin dosing and permits targeting an acceptable level of toxicity. Patients who are elderly, have a poor performance status, or have a history of extensive pretreatment have a higher risk of toxicity even when dosage is calculated with these methods, but the safety of drug administration has been enhanced. In the combination of carboplatin and paclitaxel, AUC-based dosing has helped to maximize the dose intensity of carboplatin. Dosages some 30% higher than those using a dosing strategy based solely on body surface area may safely be used. A determination of whether this approach to dosing improves outcomes will require a randomized trial.
The other toxicities of carboplatin are generally milder and better tolerated than those of cisplatin. Nausea and vomiting, although frequent, are less severe, shorter in duration, and more easily controlled with standard antiemetics (i.e., prochlorperazine [Compazine]), dexamethasone, lorazepam) than that after cisplatin treatment. Renal impairment is infrequent, although alopecia is common, especially with the paclitaxel-containing combinations. Neurotoxicity is also less common than with cisplatin, although it is observed more frequently with the increasing use of high-dose regimens. Ototoxicity is also less common.
Oxaliplatin
The dose-limiting toxicity of oxaliplatin is sensory neuropathy, a characteristic of all DACH-containing platinum derivatives. This side effect takes two forms. First, a tingling of the extremities, which may also involve the perioral region, that occurs early and usually resolves within a few days. With repeated dosing, symptoms may last longer between cycles, but do not appear to be cumulative or of long duration. Laryngopharyngeal spasms and cold dysesthesias have also been reported but are not associated with significant respiratory symptoms and can be prevented by prolonging the duration of infusion. A second neuropathy, more typical of that seen with cisplatin, affects the extremities and increases with repeated doses. Definitive physiologic characterization of oxaliplatin-induced neuropathy has proven difficult in large studies. Electromyograms performed in six patients treated by Extra et al.83revealed an axonal sensory neuropathy, but nerve conduction velocities were unchanged. Specimens from peripheral nerve biopsies performed in this study showed decreased myelination and replacement with collagen pockets. The neurologic effects of oxaliplatin appear to be cumulative in that they become more pronounced and of greater duration with successive cycles; however, unlike those of cisplatin, they are reversible with drug cessation. In a review of 682 patient experiences, Brienza et al.84 reported that 82% of patients who experienced grade 2 neurotoxicity or higher had their symptoms regress within 4 to 6 months. In a larger adjuvant trial, de Gramont et al.85 reported that 12% of patients had grade 3 toxicity at the end of a 6-month treatment period and that the majority of these patients had relief, but not always complete resolution of the symptoms, by 1 year later. The persistence of the neurotoxicity has led to approaches to ameliorate it, including the use of protective agents. The use of calcium and magnesium salts intravenously before and after each infusion has been shown to be ineffective. Ototoxicity is not observed with oxaliplatin. Nausea and vomiting do occur and generally respond to 5-HT3 antagonists. Myelosuppression is uncommon and is not severe with oxaliplatin as a single agent, but it is a feature of combinations including this drug. Oxaliplatin therapy is not associated with nephrotoxicity.
REFERENCES
1. Rosenberg B, VanCamp L, Trosko J, et al. Platinum compounds: a new class of potent antitumor agents. Nature 1969;222:385–386.
2. Rosenberg B. Fundamental studies with cisplatin. Cancer 1985;55:2303–23l6.
3. Cvitkovic E, Spaulding J, Bethune V, et al. Improvement of cis-dichlorodiammineplatinum (NSC 119875): therapeutic index in an animal model. Cancer 1977;39:1357–1361.
4. Hayes D, Cvitkovic E, Golbey R, et al. High dose cis-platinum diamine dichloride: amelioration of renal toxicity by mannitol diuresis. Cancer 1977;39:1372–1381.
5. Roberts J, Thomson A. The mechanism of action of antitumor platinum compounds. Nucleic Acids Res 1979;22:71–133.
6. Martin R. Platinum complexes: hydrolysis and binding to N(7) and N(1) of purines. In: Lippert B, ed. Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug. Zurich: Verlag Helvetica Chimica Acta; 1999:183.
7. Harrap K. Preclinical studies identifying carboplatin as a viable cisplatin alternative. Cancer Treat Rev 1985;12:A21–A33.
8. Harrap K. Initiatives with platinum- and quinazoline-based antitumor molecules—Fourteenth Bruce F. Cain Memorial Award Lecture. Cancer Res 1995;55:2761–2768.
9. Calvert A, Newell D, Gumbrell L, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748–1756.
10. Egorin M, Echo DV, Olman E, et al. Prospective validation of a pharmacologically based dosing scheme for the cis-diamminedichloroplatinum(II) analogue diamminecyclobutanedicarboxylatoplatinum. Cancer Res 1985;45:6502–6506.
11. Connors T, Jones M, Ross W, et al. New platinum complexes with anti-tumour activity. Chem Biol Interact 1972;5:415–424.
12. Burchenal J, Kalaker K, Dew K, et al. Rationale for development of platinum analogs. Cancer Treat Rep 1979;63:1493–1498.
13. Kidani Y, Inagaki K, Tsukagoshi S. Examination of antitumor activities of platinum complexes of 1,2-diaminocyclohexane isomers and their related complexes. Gann 1976;67:921–922.
14. Burchenal J, Irani G, Kern K, et al. 1,2-Diaminocyclohexane platinum derivatives of potential clinical value. Rec Res Cancer Res 1980;74:146–155.
15. Rixe O, Ortuzar W, Alvarez M, et al. Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute’s anticancer drug screen panel. Biochem Pharmacol 1996;52:1855–1865.
16. Shimada M, Itamochi H, Kigawa J. Nedaplatin: a cisplatin derivative in cancer therapy. Cancer Manag Res 2013;5:67–76.
17. Fojo T, Farrell N, Ortuzar W, et al. Identification of non-cross-resistant platinum compounds with novel cytotoxicity profiles using the NCI anticancer drug screen and clustered image map visualizations. Crit Rev Oncol Hematol 2005;53:25–34.
18. Bates SE, Amiri-Kordestani L, Giaccone G. Drug development: portals of discovery. Clin Cancer Res 2012;18:23–32.
19. Kelland L. The development of orally active platinum drugs. In: Lippert B, ed. Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug. Zurich: Verlag Helvetica Chimica Acta; 1999:497.
20. Farrell N, Qu Y, Bierbach U, et al. Structure-activity relationships within di- and trinuclear platinum phase-I clinical anticancer agents. In: Lippert B, ed. Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug. Zurich: Verlag Helvetica Chimica Acta; 1999;477–496.
21. Holford J, Sharp S, Murrer B, et al. In vitro circumvention of cisplatin resistance by the novel sterically hindered platinum complex AMD473. Br J Cancer 1998;77:366–373.
22. Flaherty KT, Stevenson JP, Redlinger M, et al. A phase I, dose escalation trial of ZD0473, a novel platinum analogue, in combination with gemcitabine. Cancer Chemother Pharmacol 2004;53:404–408.
23. Park GY, Wilson JJ, Song Y, et al. Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile. Proc Natl Acad Sci U S A 2012;109:11987–11992.
24. Eastman A. The formation, isolation and characterization of DNA adducts produced by anticancer platinum complexes. Pharmacol Ther 1987;34:155–166.
25. Zhu G, Song L, Lippard SJ. Visualizing inhibition of nucleosome mobility and transcription by cisplatin-DNA interstrand crosslinks in live mammalian cells. Cancer Res 2013;73:4451–4460.
26. Martens-de Kemp SR, Dalm SU, Wijnolts FM, et al. DNA-bound platinum is the major determinant of cisplatin sensitivity in head and neck squamous carcinoma cells. PLoS One 2013;8:e61555.
27. Blommaert F, van Kijk-Knijnenburg H, Dijt F, et al. Formation of DNA adducts by the anticancer drug carboplatin: different nucleotide sequence preferences in vitro and in cells. Biochemistry 1995;34:8474–8480.
28. Scheef E, Briggs J, Howell S. Molecular modeling of the intrastrand guanine-guanine DNA adducts produced by cisplatin and oxaliplatin. Mol Pharmacol 1999;56:633–643.
29. Enoiu M, Jiricny J, Schärer OD. Repair of cisplatin-induced DNA interstrand crosslinks by a replication-independent pathway involving transcription-coupled repair and translesion synthesis. Nucleic Acids Res 2012;40:8953–8964.
30. Zhu G, Song L, Lippard SJ. Visualizing inhibition of nucleosome mobility and transcription by cisplatin-DNA interstrand crosslinks in live mammalian cells. Cancer Res 2013;73:4451–4460.
31. Sorenson C, Eastman A. Mechanism of cis-diamminedichloroplatinum (II)-induced cytotoxicity: role of G2 arrest and DNA double-strand breaks. Cancer Res 1988;48:4484–4488.
32. Toney J, Donahue B, Kellett P, et al. Isolation of cDNAs encoding a human protein that binds selectively to DNA modified by the anticancer drug cis-diamminedichloroplatinum. Proc Natl Acad Sci U S A 1989;86:8328–8332.
33. Bruhn S, Pil P, Essigmann J, et al. Isolation and characterization of human cDNA clones encoding a high mobility group box protein that recognizes structural distortions to DNA caused by binding of the anticancer agent cisplatin. Proc Natl Acad Sci U S A 1989;89:2307–2311.
34. Hughes EN, Engelsberg BN, Billings PC. Purification of nuclear proteins that bind to cisplatin-damaged DNA. Identity with high mobility group proteins 1 and 2. J Biol Chem 1992;267:13520–13527.
35. Ramachandran S, Temple BR, Chaney SG, et al. Structural basis for the sequence-dependent effects of platinum-DNA adducts. Nucleic Acids Res 2009;37:2434–2448.
36. Ramachandran S, Temple B, Alexandrova AN, et al. Recognition of platinum-DNA adducts by HMGB1a. Biochemistry 2012;51:7608–7617.
37. Fink D, Zheng H, Nebel S, et al. In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. Cancer Res 1997;57:1841–1845.
38. Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 2007;7:573–584.
39. Vasilevskaya IA, Rakitina TV, O’Dwyer PJ. Quantitative effects on c-Jun N-terminal protein kinase signaling determine synergistic interaction of cisplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines. Mol Pharmacol 2004;65:235–243.
40. Vasilevskaya IA, Selvakumaran M, O’Dwyer PJ. Disruption of signaling through SEK1 and MKK7 yields differential responses in hypoxic colon cancer cells treated with oxaliplatin. Mol Pharmacol 2008;74:246–254.
41. Maestre N, Tritton TR, Laurent G, et al. Cell surface-directed interaction of anthracyclines leads to cytotoxicity and nuclear factor kappaB activation but not apoptosis signaling. Cancer Res 2001;61:2558–2561.
42. Roodhart JM, Daenen LG, Stigter EC, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 2011;20:370–383.
43. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 regulates cancer inflammation and induces regression of pancreatic carcinoma in mice and humans. Science 2011;331:1612–1616.
44. Galluzzi L, Senovilla L, Vitale I, et al. Molecular mechanisms of cisplatin resistance. Oncogene 2012;31:1869–1883.
45. Lin X, Okuda T, Holzer A, et al. The copper transporter CTR1 regulates cisplatin uptake in Saccharomyces cerevisiae. Mol Pharmacol 2002;62:1154–1159.
46. Blair BG, Larson CA, Safaei R, et al. Copper transporter 2 regulates the cellular accumulation and cytotoxicity of cisplatin and carboplatin. Clin Cancer Res 2009;15:4312–4321.
47. Samimi G, Varki NM, Wilczynski S, et al. Increase in the expression of the copper transporter ATP7A during platinum drug-based treatment is associated with poor survival in ovarian cancer patients. Clin Cancer Res 2003;9:5853–5859.
48. Britten RA, Green JA, Broughton C, et al. The relationship between nuclear glutathione levels and resistance to melphalan in human ovarian tumour cells. Biochem Pharmacol 1991;41:647–649.
49. Mistry P, Kelland L, Abel G, et al. The relationships between glutathione, glutathione-S-transferase and cytotoxicity of platinum drugs and melphalan in eight human ovarian carcinoma cell lines. Br J Cancer 1991;64:215–220.
50. Godwin A, Meister A, O’Dwyer P, et al. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase in glutathione synthesis. Proc Natl Acad Sci U S A 1992;89:3070–3074.
51. Hamilton T, Winker M, Louie K, et al. Augmentation of adriamycin, melphalan and cisplatin cytotoxicity in drug-resistant and sensitive human ovarian cancer cell lines by buthionine sulfoximine mediated glutathione depletion. Biochem Pharmacol 1985;34:2583–2586.
52. Koberle B, Grimaldi K, Sunters A, et al. DNA repair capacity and cisplatin sensitivity of human testis tumour cells. Int J Cancer 1997;70:551–555.
53. Martin LP, Hamilton TC, Schilder RJ. Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 2008;14:1291–1295.
54. Selvakumaran M, Piscarcik DA, Bao R, et al. Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res 2003;63:1311–1316.
55. Hubner RA, Riley RD, Billingham LJ, et al. Excision repair cross-complementation group 1 (ERCC1) status and lung cancer outcomes: a meta-analysis of published studies and recommendations. PLoS One 2011;6:e25164.
56. De Dosso S, Zanellato E, Nucifora M, et al. ERCC1 predicts outcome in patients with gastric cancer treated with adjuvant cisplatin-based chemotherapy. Cancer Chemother Pharmacol 2013;72:159–165.
57. Squires MH 3rd, Fisher SB, Fisher KE, et al. Differential expression and prognostic value of ERCC1 and thymidylate synthase in resected gastric adenocarcinoma. Cancer 2013;119:3242–3250.
58. Yamada Y, Boku N, Nishina T, et al. Impact of excision repair cross-complementing gene 1 (ERCC1) on the outcomes of patients with advanced gastric cancer: correlative study in Japan Clinical Oncology Group Trial JCOG9912. Ann Oncol 2013;24:2560–2565.
59. Friboulet L, Olaussen KA, Pignon JP, et al. ERCC1 isoform expression and DNA repair in non–small-cell lung cancer. N Engl J Med 2013;368:1101–1110.
60. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434:913–917.
61. Farmer H, McCabe1 N, Lord C, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917–921.
62. Edwards SL, Brough R, Lord CJ, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 2008;451:1111–1116.
63. Sakai W, Swisher EM, Karlan BM, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 2008;451:1116–1121.
64. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncology 2011;12:852–861.
65. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008;132:27–42.
66. Matthew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer 2007;7:961–967.
67. Amaravadi RK, Yu D, Lum JJ, et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007;117:326–336.
68. Duffull S, Robinson B. Clinical pharmacokinetics and dose optimization of carboplatin. Clin Pharmacokinet 1997;33:161–183.
69. Harland S, Newell D, Siddik Z, et al. Pharmacokinetics of cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function. Cancer Res 1984;44:1693–1697.
70. Graham MA, Lockwood GF, Greenslade D, et al. Clinical pharmacokinetics of oxaliplatin: a critical review. Clin Cancer Res 2000;6:1205–1218.
71. Gamelin E, Bouil A, Boisdron-Celle M, et al. Cumulative pharmacokinetic study of oxaliplatin, administered every three weeks, combined with 5-fluorouracil in colorectal cancer patients. Clin Cancer Res 1997;3:891–899.
72. Extra JM, Marty M, Brienza S, et al. Pharmacokinetics and safety profile of oxaliplatin. Semin Oncol 1998;25:13–22.
73. Chatelut E, Canal P, Brunner V, et al. Prediction of carboplatin clearance from standard morphological and biological patient characteristics. J Natl Cancer Inst 1995;87:573–580.
74. Jodrell D, Egorin M, Canetta R, et al. Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 1992;10:520–528.
75. Reyno L, Egorin M, Canetta R, et al. Impact of cyclophosphamide on relationships between carboplatin exposure and response or toxicity when used in the treatment of advanced ovarian cancer. J Clin Oncol 1993;11:1156–1164.
76. Shen DW, Pouliot LM, Hall MD, et al. Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev 2012;64:706–721.
77. Ma J, Verweij J, Planting A, et al. Current sample handling methods for measurement of platinum-DNA adducts in leucocytes in man lead to discrepant results in DNA adduct levels and DNA repair. Br J Cancer 1995;71:512–517.
78. Schellens J, Ma J, Planting A, et al. Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours. Br J Cancer 1996;73:1569–1575.
79. Ozols R, Corden B, Jacob J, et al. High-dose cisplatin in hypertonic saline. Ann Intern Med 1984;100:19–24.
80. Howell S, Pfeifle C, Wung W, et al. Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection. Cancer Res 1983;43:1426–1431.
81. Alberts D, Liu P, Hannigan E, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950–1955.
82. Solomon B, Soulen M, Baum R, et al. Chemoembolization of hepatocellular carcinoma with cisplatin, doxorubicin, mitomycin-C, Ethiodol, and polyvinyl alcohol: prospective evaluation of response and survival in a US population. J Vasc Interv Radiol 1999;10:793–798.
83. Extra J, Marty M, Brienza S, et al. Pharmacokinetics and safety profile of oxaliplatin. Semin Oncol 1998;25:13–22.
84. Brienza S, Vignoud J, Itzhaki M, et al. Oxaliplatin (L-OHP): global safety in 682 patients. Proc Am Soc Clin Oncol 1995;14:209.
85. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343–2351.