Cisplatin: Current Status and New Developments

Laboratories.

I

PRECLINICAL STUDIES

Outline

Chapter 1: CISPLATIN: A PRECLINICAL OVERVIEW

Chapter 2: CISPLATIN: ITS HISTORY AND POSSIBLE MECHANISMS OF ACTION

Chapter 3: EFFECTS OF CISPLATIN ON DNA AND THE POSSIBLE RELATIONSHIPS TO CYTOTOXICITY AND MUTAGENICITY IN MAMMALIAN CELLS

Chapter 4: THE LETHAL ACTIVITY OF PLATINUM COMPOUNDS IN COMBINATION WITH PYRIMIDINE DERIVATIVES

Chapter 5: REPAIR OF cis-PLATINUM (II) DIAMMINE DICHLORIDE-INDUCED DNA DAMAGE AND CELL SENSITIVITY

Chapter 6: ULTRASTRUCTURAL EFFECTS OF CISPLATIN

Chapter 7: RATIONALE OF COMBINATION CHEMOTHERAPY

Chapter 8: A REVIEW OF INTERACTIONS BETWEEN PLATINUM COORDINATION COMPLEXES AND IONIZING RADIATION: IMPLICATIONS FOR CANCER THERAPY

Chapter 9: ANTITUMOR PLATINUM COMPLEXES: STRUCTURE-ACTIVITY RELATIONSHIPS

Chapter 10: ANTITUMOR ACTIVITY OF PLATINUM ANALOGS

Chapter 11: ANTITUMOR ACTIVITY OF CISPLATIN ANALOGS

Chapter 12: ANTITUMOR, TOXIC AND BIOCHEMICAL PROPERTIES OF CISPLATIN AND EIGHT OTHER PLATINUM COMPLEXES

Chapter 13: IN VITRO INTERACTION OF COVALENTLY LINKED CLOSED CIRCULAR DNA WITH THE SECOND-GENERATION PLATINUM COMPOUNDS

Chapter 14: TOXIC SIDE EFFECTS OF PLATINUM ANALOGS

Chapter 15: APPROACHES TO STUDIES OF PLATINATE TOXICITIES

Chapter 16: MORPHOLOGICAL MANIFESTATIONS OF CISPLATIN ANALOGS IN RATS: AN ULTRASTRUCTURAL STUDY

Chapter 17: RADIOPHARMACOKINETICS OF CISPLATIN

Chapter 18: REACTIONS OF CISPLATIN WITH HUMAN PLASMA AND PLASMA FRACTIONS

Chapter 19: PHYSICAL COMPATIBILITY AND CHEMICAL STABILITY OF CISPLATIN IN VARIOUS DILUENTS AND IN LARGE-VOLUME PARENTERAL SOLUTIONS

Chapter 1

CISPLATIN: A PRECLINICAL OVERVIEW

Archie W. Prestayko

Publisher Summary

Cisplatin (cis-diamminedichloroplatinum II) is one of the group of platinum coordination complexes, which possess antibiotic activity. Cisplatin causes the inhibition of growth of Escherichia coli and transforms the bacteria into long filamentous structures. Cisplatin has a major role in the chemotherapy of several human malignancies. It is a water-soluble square planar coordination complex containing a central platinum atom surrounded by two chloride atoms and two ammonia moieties. The antitumor activity of the complex is much greater when the chloride and ammonia moieties are in the cis position compared to the trans position. As a prime mechanism of the inhibition of tumor growth by cisplatin appears to be the inhibition of DNA synthesis, it has been suggested that the cis configuration of cisplatin favors the formation of intrastrand crosslinks in DNA. Studies have suggested that the intrastrand crosslinks are formed through the N-7 position of adjacent guanine bases, resulting in the local denaturation of the DNA double helix.

I. Introduction

II. Mechanism of Action

III. Pharmacology

IV. Antitumor Activity

V. Toxicity

VI. Cisplatin Analogs

VII. Conclusion

References

I. INTRODUCTION

Cisplatin (cis-diamminedichloroplatinum II) is one of a group of platinum coordination complexes that was first shown by Rosenberg et al. (1965) to possess antibiotic activity. This study demonstrated that cisplatin caused inhibition of growth of Escherichia coli and transformed the bacteria into long filamentous structures. Subsequent studies by Rosenberg et al. (1969) first established the antitumor activity of cisplatin in experimental animal tumors. In 1972 the National Cancer Institute introduced cisplatin into clinical trials. Cisplatin currently has a major role in the chemotherapy of several human malignancies.

II. MECHANISM OF ACTION

Cisplatin is a water-soluble square planar coordination complex containing a central platinum atom surrounded by two chloride atoms and two ammonia moieties (Fig. 1). The antitumor activity of the complex is much greater when the chloride and ammonia moieties are in the cis position compared to the trans position. Since a prime mechanism of inhibition of tumor growth by cisplatin appears to be inhibition of DNA synthesis (Howle and Gale, 1970; Taylor et al., 1976), it has been suggested that the cis configuration of cisplatin favors the formation of intrastrand crosslinks in DNA (Roberts, 1974; Roberts and Pascoe, 1972; Rosenberg, 1971; Roos and Arnold, 1977; Thomson and Mansy, 1972). Recent studies have suggested that the intrastrand crosslinks may be formed through the N-7 position of adjacent guanine bases, resulting in local denaturation of the DNA double helix (Butour and Macquet, 1977; Kelman and Buchbinder, 1978).

Fig. 1 Cisplatin (cis-diamminedichloroplatinum II).

The presence of interstrand crosslinks in DNA after reaction with either cisplatin or the trans isomer has been demonstrated (Zwelling et al., 1978; Pascoe and Roberts, 1974). However, since the trans isomer is inactive as an antitumor agent, the significance of such interstrand crosslinks is questionable. Zwelling et al. (1978) have also demonstrated the presence of protein-DNA crosslinks after treatment with cisplatin. The significance of these reactions is also not understood.

III. PHARMACOLOGY

Initial pharmacokinetic studies of cisplatin in animals indicated that cisplatin was lost from the blood in a biphasic manner (Litterst et al., 1976; Litterst et al., 1977). The t½α was less than 1 hr and the t½β was 4–5 days in dogs (Fig. 2) and 2 days in rats (Litterst et al., 1976). Administration of diuretics and intravenous fluids to animals prior to cisplatin administration did not significantly alter the pharmacokinetics of this drug but did significantly decrease the urine concentration of platinum (Cvitkovic et al., 1977). This method of administration reduced the nephrotoxic potential of cisplatin and served as a basis for subsequent methods to reduce cisplatin-induced nephrotoxicity in patients (reviewed by Prestayko et al., 1979). The plasma elimination half-life (t½β) in humans ranged from 58 to 73 hr (DeConti et al., 1973; Smith and Taylor, 1974; Lange et al., 1973).

Fig. 2 Plasma concentration and urinary excretion of platinum following single IV administration of cisplatin to dogs. (from Litterst et al., 1976)

Cisplatin can react with water molecules in plasma to form monoaquo and diaquo species that then may react with various nucleophiles. It has become apparent that measurement of total platinum by atomic absorption spectrophotometry is inadequate to describe the pharmacology of cisplatin. Recently a method has been described that measures plasma levels of platinum as free drug (filterable) and as protein-bound drug (nonfilterable) (Bannister et al., 1978; Bannister et al., 1977). Further refinement of this method has made possible the measurement of plasma concentration of parent drug and other species (metabolites or breakdown products) by high-pressure liquid chromatography (Chang et al., 1978; Repta and Long, this volume). The results of these and another study (Patton et al., 1978) indicated that after a bolus injection plasma levels of filterable platinum-containing species decline in an apparent biphasic mode with a t½β of 32–53.5 min. The t½α of total plasma platinum observed in earlier studies (DeConti et al., 1973, Lange et al., 1973; Smith and Taylor, 1974) probably represents the plasma clearance of filterable platinum. Within 3 hr after administration of cisplatin, approximately 90% of the platinum in the plasma was protein bound and nonfilterable. In an in vitro study of serum protein binding of cisplatin, LeRoy et al. (1979) demonstrated that the amount of filterable platinum decreased linearly with time of incubation during the first 10–12 hr of incubation (Fig. 3).

Fig. 3 represents percent of platinum in ultrafiltrate of a cisplatin in saline solution with time of incubation. Platinum determinations were made with atomic absorption spectrometry. (modified from LeRoy et al., 1979).

The pharmacology of cisplatin appears to be complex. The dissociation of the chloride from cisplatin allows for a number of reactive species to be formed that then may form complexes with small molecules and nucleophiles. In addition, serum protein binding, possibly via the ammonia moieties, further complicates pharmacokinetic analysis. The clarification of such reaction products of cisplatin with blood components awaits further development of sensitive analytical methods for their detection.

IV. ANTITUMOR ACTIVITY

Cisplatin has demonstrated antitumor activity in a number of experimental systems, including B-16 melanoma, Walker 256 carcinosarcoma (Kociba et al., 1970), sarcoma 180 and leukemia L1210 (Rosenberg et al., 1969), and DMBA-induced mammary tumors in rats (Welsch, 1971). In combination with other chemotherapeutic agents including methotrexate and daunomycin, cisplatin demonstrated enhanced therapeutic effects in L1210 leukemia compared to either drug used alone and also demonstrated lack of cross-resistance in alkylating-agent-resistant tumors (Gale et al., 1974; Hill et al, 1972; Walker and Gale, 1973; Woodman, 1974).

More recent studies of cisplatin in combination with radiotherapy suggest a synergistic effect in antitumor activity (Douple et al., 1977; Soloway and Sudderth, in press). Although much data have been obtained using cells in tissue culture (Douple and Richmond, 1978), the potential of cisplatin to inhibit repair of radiation-induced damage to DNA may prove to be an important aspect of enhanced tumor cell killing in vivo by these two modes of treatment.

V. Toxicity

The major toxicities of cisplatin that were observed in dogs and monkeys (Schaeppi et al., 1973) have been readily observed in patients. These include dose-limiting renal toxicity, nausea and vomiting, myelosuppression, ototoxicity, and decrease in serum electrolytes. The use of intensive intravenous hydration with concomitant diuresis has decreased the severity of cisplatin-induced nephrotoxicity. However, this method of cisplatin administration has not significantly altered the incidence or severity of the other side effects.

VI. CISPLATIN ANALOGS

Many analogs of cisplatin have been synthesized including substitution of ligands for both the ammonia and chloride groups of the molecule. A number of these compounds have been reported to possess antitumor activity in experimental animal tumors (Cleare et al., 1978; Prestayko et al., 1979). In addition many of these analogs have demonstrated significantly lower nephrotoxicity compared to cisplatin (Guarino et al., 1979; Prestayko et al., 1979).

A class of analogs that contains a 1,2-diaminocyclohexyl moiety was shown to be active in a line of L1210 leukemia cells that had developed resistance to cisplatin (Burchenal et al., 1977). One of these compounds, 1,2 diaminocyclohexyl platinum II malonate, has demonstrated antitumor activity in human tumors (Hill et al., 1977; Ribaud et al., 1979), some of which may have been resistant to cisplatin.

Another group of analogs in which platinum has a 4+ valence state (platinum IV), may possess additional activity on DNA that is different from that of the platinum II compounds (Mong et al., this volume). One such compound, bis-isopropyl, trans-dihydroxy, dichloro platinum IV, is scheduled for clinical trials in the very near future.

VII. CONCLUSION

Cisplatin and analogs show considerable promise in the chemotherapy of human neoplasms. The lack of cross-resistance with alkylating agents and the relative lack of myelosuppression makes cisplatin a useful drug to include in combination chemotherapy. Appropriate dosing schedules must still be worked out to utilize cisplatin most efficaciously and to minimize the associated toxicities.

REFERENCES

Bannister, S. J., Sternson, L. A., Repta, A. J., James, G. W. Clin. Chem. 1977; 23:2258–2262.

Bannister, S. J., Chang, Y., Sternson, L. A., Repta, A. J. Clin. Chem. 1978; 24:800–877.

Burchenal, J. H., Kalaher, K., O’Toole, T., Chisholm, J. Cancer Res. 1977; 37:3455–3457.

Butour, S. L., Macquet, J. A. Europ. J. Biochem. 1977; 78:455–463.

Chang, Y., Sternson, L. A., Repta, A. J. Analytical Letters. 1978; 11:449–460.

Cleare, M., Hydesm, P. C., Malerbi, B. W., Watkins, D. M. Biochimie. 1978; 60:835–850.

Cvitkovic, E., Spaulding, J., Bethune, C. P., Martin, J., Whitmore, W. Cancer Res. 1977; 39:1357–1361.

De Conti, R. C., Toftness, B. R., Lange, R. C., Creasey, W. A. Cancer Res. 1973; 33:1310–1315.

Douple, E. B., Richmond, R. C., Logan, M. E. J. Clin. Hematol. Oncol. 1977; 7:585–603.

Douple, E. B., Richmond, R. C. Br. J. Cancer. 1978; 37:98–102.

Gale, G. E., Walker, E. M., Jr., Atkins, L., Smith, A. B., Meischen, S. J. Res. Comm. Chem. Pathol. Pharmacol. 1974; 7:529–538.

Guarino, A., Miller, D. S., Arnold, S. T., Pritchard, J. B., Davis, R. D., Urbanek, M. A., Miller, T. J., Litterst, C. L. Cancer Treat. Rep. 1979; 63:1475–1483.

Hill, J. M., Cardona, F. A., Loeb, E., MacLellan, A. S., Hill, N. O., Khan, A. Wadley Med. Bul. 1972; 2:45.

Hill, J. M., Loeb, E., Pardue, A. S., Hill, N. O., Khan, A., King, J. J. J. Clin. Hematol. Oncol. 1977; 7:681–700.

Howie, J. A., Gale, G. R. Biochem. Pharmacol. 1970; 19:2757–2762.

Kelman, A. D., Buchbinder, M. Biochimie. 1978; 60:893–899.

Kociba, R. J., Sleight, S. D., Rosenberg, B. Cancer Chemother. Rep. 1970; 54:325–328.

Lange, R. C., Spencer, R. P., Harder, H. C. J. Nucl. Med. 1973; 14:191–195.

LeRoy, A. F., Lutz, R. J., Dedrick, R. L., Litterst, C. L., Guarino, A. M. Cancer Treat. Rep. 1979; 63:59–71.

Litterst, C. L., Gram, T. E., Dedrick, R. L., LeRoy, A. F., Guarino, A. M. Cancer Res. 1976; 36:2340–2344.

Litterst, C. L., Torress, I. J., Guarino, A. M. J. Clin. Hematol. Oncol. 1977; 7:169–179.

Pascoe, J. M., Roberts, J. J. Biochem. Pharmacol. 1974; 23:1762–1768.

Patton, T. F., Himmelstein, K. J., Belt, R., Bannister, S. J., Sternson, L. A., Repta, A. J. Cancer Treat. Rep. 1978; 62:1359–1362.

Prestayko, A. W., Bradner, W. T., Huftalen, J. B., Rose, W. C., Schurig, J. E., Cleare, M. J., Hydes, P. A., Crooke, S. T. Cancer Treat. Rep. 1979; 63:1503–1507.

Ribaud, P., Alcock, N., Burchenal, J. H., Young, C., Muggia, F., Mathé, G. Proc. Amer. Assoc. Clinc. Oncol. 1979; 20:336.

Roberts, J. J. Platinum Coordination Complexes in Cancer Chemotherapy. Heidelberg: Springer-Verlag, 1974; 79–97.

Roberts, J. J., Pascoe, J. M. Advances in Antimicrobial and Antineoplastic Chemotherapy; II. Univ. Park Press, Baltimore, 1972:249–252.

Roos, I. A., Arnold, M. J Clin. Hematol. Oncol. 1977; 7:374–390.

Rosenberg, B. Plat. Med. Rev. 1971; 15:42–51.

Rosenberg, B., VanCamp, L., Krigas, T. Nature. 1965; 205:698–699.

Rosenberg, B., VanCamp, L., Trosko, J., Mansour, V. H. Nature. 1969; 222:385–386.

Schaeppi, U., Heyman, I. A., Fleischman, R. W., Rosenkrantz, H., Ilievski, V., Phelan, R. A., Cooney, D. A., Davis, R. D. Toxic. Appl. Pharmacol. 1973; 25:230–241.

Smith, P. H., Taylor, D. M. J. Nucl. Med. 1974; 15:349–351.

Soloway, M. S., Sudderth, B. Int. J. Radiation Oncol. Biol. Phys. 1979;

Taylor, D. M., Tew, K. D., Jones, J. D. Europ. J. Cancer. 1976; 12:249–254.

Thomson, A. J., Mansy, S. Advances in Antimicrobial and Antineoplastic Chemotherapy; III. Baltimore University Press, Baltimore, 1972:199–203.

Walker, E. M., Jr., Gale, G. R. Res. Comm. Chem. Pathol. Pharmacol. 1973; 6:419–425.

Welsch, C. W. Proc. Amer. Assoc. Cancer Res. 1971; 12:25.

Woodman, R. J. Cancer Chemother. Rep. 1974; 4:45–52.

Zwelling, L. A., Kohn, K. W., Ross, W. E., Ewig, R. A.G., Anderson, T. Cancer Res. 1978; 38:1762–1768.

Chapter 2

CISPLATIN: ITS HISTORY AND POSSIBLE MECHANISMS OF ACTION

Barnett Rosenberg

Publisher Summary

Cisplatin (cis-dichlorodiammineplatinum II) is the first member of a new class of potent anticancer drugs, the metal coordination complexes, to enter general use in cancer chemotherapy. The drug has been proved to be effective alone or in combination for the treatment of a wide variety of solid cancers in man. Evidence suggests that it is curative for testicular cancers and ovarian cancers. It is also palliative in the treatment of cancers of the head and neck, bladder, prostate, lung, and cervix and in some pediatric cancers. The major toxic side effects of the drug are damage to the kidney, nausea, and vomiting. The hydration of the patient, with or without concomitant diuretics, ameliorates the kidney toxicity so well that in some clinical reports, it is no longer considered to be the dose-limiting side effect. The nausea and vomiting due to this drug are extreme, ubiquitous, and long lasting. Evidence has been reported indicating that nonstandard drugs such as marijuana, metaclopromide, and droperidol are effective in reducing the nausea and vomiting to an acceptable level.

I. Introduction

II. History of the Discovery

III. Mechanisms of Anticancer Actions

References

I. INTRODUCTION

Cisplatin (cis-dichlorodiammineplatinum II) is the first member of a new class of potent anticancer drugs, the metal coordination complexes, to enter general use in cancer chemotherapy. This represents a reintroduction into medicine of such metal complexes in recent times. The drug has now been proved to be effective alone or in combination for the treatment of a wide variety of solid cancers in man. Evidence suggests that it may be curative for testicular cancers and ovarian cancers. It is also palliative in the treatment of cancers of the head and neck, bladder, prostate, lung, cervix, and in some pediatric cancers. Many clinical trials are prevalent throughout the world, testing both the application of this drug to other cancers and the improved protocols with higher activity against the known responsive cancers.

The major toxic side effects of the drug are damage to the kidney and nausea and vomiting. Hydration of the patient, with or without concomitant diuretics, ameliorates the kidney toxicity so well that in some clinical reports it is no longer considered to be the dose-limiting side effect. The nausea and vomiting due to this drug are extreme, ubiquitous, and long lasting. Standard antiemetics are of little value in diminishing these effects. However, some recent evidence has been reported indicating that nonstandard drugs such as marijuana, metaclopromide, and droperidol may be effective in reducing the nausea and vomiting to an acceptable level. Slow infusion of the drug (24 hr) also appears to mitigate these effects. It is generally believed that the nausea and vomiting arise from the action of the drug on the chemoreceptor trigger zone of the brain rather than from a direct action in the gastrointestinal tract.

The number of minor side effects continues to increase with further clinical experimentation with this drug. These now include tinnitus, deafness, myelosuppression, peripheral neuropathy, and hypomagnesemia. We are now trying to develop techniques to limit or eliminate these undesirable, but not life threatening, side effects.

Cisplatin was shown in many early studies in animals to act either additively or synergistically with most other anticancer drugs. Since its side effects do not appear to overlap greatly with those due to other drugs, it is likely that cisplatin will be used with a high degree of safety in combination chemotherapy. There is reason to believe that such combinations with cisplatin may be effective in the treatment of human cancers, even those where cisplatin as a single agent has not been shown to have a significant degree of activity. However, there have been some combinations tested that do not appear to provide any greater response rates in particular cancers than does the cisplatin drug alone. Therefore, one cannot wholly accept this generalization yet.

Cisplatin is the first of the drugs shown to be active in the initial animal studies to move into the clinic. It is reasonable to expect that analogs of this drug may be, or indeed have been, found with superior activities in animal studies, and with either lesser toxicities or different spectra of toxicities. Indeed, approximately 180 such analogs out of over 1000 tested have met the criteria of activity against one or more tumor screen systems. As of late 1979, five analog structures are in the preliminary toxicologic and pharmacologic stages of development or are already in phase I clinical trials. The success rate for finding active platinum coordination complexes is far higher (∼18%) than for the purely organic chemicals (∼5%) and does suggest that we should intensify the search where the light is brightest. Still poorly tested are coordination complexes of metals other than platinum. These represent a large and potentially rich field for further developments.

With the advent of a new class of active anticancer drugs, a novel opportunity arises to use the structure-activity relationship and the study of their molecular biology to develop some understanding of the mechanism(s) of action of anticancer drugs. We remain perplexed, at this time, as to why we have been so successful in developing potent anticancer drugs, and indeed in curing many patients, without having any substantial knowledge as to how these drugs act so selectively, either alone or in conjunction with the host’s immunologic system, to destroy cancer cells with so little effect upon the other major tissues of the body. This selectivity is the central problem of anticancer drug action.

In this paper I will describe briefly the historic aspects of the discovery and the development of the platinum anticancer drugs, and I will describe some hypotheses that are presently being studied in my laboratory and elsewhere to approach the problem of the mechanisms of action.

II HISTORY OF THE DISCOVERY

The discovery of the biologic actions of the simple platinum coordination complexes is a textbook case of serendipity. The motivation for the experiments came from a desire to study the effects of electric fields on cells growing in culture. This story has been told in detail elsewhere (Rosenberg, 1978). The first signal of biologic activity occurred when E. coli were incubated in a chemically defined growth medium containing ammonium chloride as a nitrogen source, in a chamber containing two platinum electrodes. When an alternating voltage was applied across the electrodes it was noted that the density of bacteria in the chamber (a continuous culture apparatus) decreased with time. With the voltage turned off, there was a regrowth of the bacteria. This process could be repeated ad infinitum. A further surprise occurred when the cells emerging in the effluent were examined under the light microscope. With the field on, the normal rods (∼1 × 5 μ) were gone. Instead, the bacteria were all in the form of very long filaments.

By separating the bacterial chamber from the platinum electrodes containing chamber through which the nutrient media was first pumped, the same effect was noted. This meant that long-lasting chemical species were produced by electrolysis at the platinum electrodes, and it was these chemicals that caused the filamentation of the bacteria. After 2 years of work it was determined that these chemical species are cisplatin and/or its platinum (IV) analog. This chemical had first been synthesized in 1845 and was known as Peyrone’s chloride. The elucidation of its structure by Werner was a major contribution to the establishment of a firm basis for coordination chemistry. Thus, cisplatin has indeed had a noble history. Our work showed for the first time that this class of chemicals also had significant biologic actions.

Other effects of platinum complexes on bacteria were studied (Rosenberg et al., 1967a; Rosenberg et al., 1967b;Renshaw and Thomson, 1967). It was generally concluded that charged species in solution were potent bacteriocides, whereas the neutral species (such as cisplatin) inhibit cell division without marked effects on the growth rate, thus leading to filamentation. The neutral species were also shown to be very effective in inducing derepression of latent viral genomic information in lysogenic bacteria (Reslova, 1971–72; Reslova-Vasilukova, 1974). Near the termination of these studies we made the intuitive jump to the conclusion that these chemical species may, by virture of their action in bacterial cells, also inhibit cell division in rapidly growing cancer cells. To test this we first determined the nontoxic doses tolerated by mice (LD50 ≅ 13 mg/kg). The first tumor system used was the solid sarcoma 180 in ICR mice. The drug, and a number of analogs, completely inhibited the development of this tumor when given ip 1 day after inoculation of the tumor. These results led to a test at the National Cancer Institute against the L1210 tumor in BDF1 mice. The drug passed the activity criteria, and the results were published (Rosenberg et al., 1969). The drug has subsequently been tested and found to be active against a wide variety of animal tumor systems. The best results of these tests are presented in Table I. These results lead to the following