Cancer Chemotherapy and Pharmacology

, Volume 25, Issue 6, pp 395–404 | Cite as

A strategy for the development of two clinically active cisplatin analogs: CBDCA and CHIP

  • Brenda J. Foster
  • Bonnie J. Harding
  • Mary K. Wolpert-DeFilippes
  • Lawrence Y. Rubinstein
  • Kathleen Clagett-Carr
  • Brian Leyland-Jones
Original Articles Cisplatin, Carboplatin, Iproplatin, Toxicology


The antitumor agent cisplatin has a broad antitumor spectrum and has been incorporated into regimens that are curative for some malignant diseases. However, one of the major limitations to its clinical usefulness is the incidence of severe toxicities involving several major organ systems. Therefore, much enthusiasm has been generated for the development of cisplatin analogs that demonstrate an improved therapeutic index in some preclinical models. The two most promising analogs are CBDCA (carboplatin) and CHIP (iproplatin). The preclinical and early clinical trial results have demonstrated that these two compounds show activity in cisplatin-responsive tumors. The preclinical background providing the rationale for the clinical development of these two analogs is described. We suggest a means of screening for each analog's clinical antitumor activity and determining the analogs' utility against specific malignant diseases compared with that of the parent compound or standard treatment.


Carboplatin Malignant Disease Preclinical Model Therapeutic Index Antitumor Agent 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Alberts D, Green S, Hannigan E, O'Tools R, Mason-Liddil N, Surwit E, Stock-Novack D, Goldberg R, Malviya V, Nahhas W (1989) Improved efficacy of carboplatin (Carbo-P)/cyclophosphamide (CPA) vs cisplatin (CisP)/CPA: preliminary report of a phase III, randomized trial in stages III–IV, suboptimal ovarian cancer (OV CA). Proc Am Soc Clin Oncol 8: 151Google Scholar
  2. 2.
    Arseneau JC, Hatch K, Stehman F, Blessing J (1985) Phase II study of carboplatin in advanced squamous cell carcinoma of cervix. Proc Am Soc Clin Oncol 4: 120Google Scholar
  3. 3.
    Basolo F, Pearson RG (1962) Thetrans effect in metal complexes. Prog Inorg Chem 4: 381–453Google Scholar
  4. 4.
    Bradner WT, Rose WC, Huftalen JB (1980) Antitumor activity of platinum analogs. In: Prestayko AW, Crooke ST, Carter SK (eds) Cisplatin — current status and new developments. Academic, New York, pp 171–182Google Scholar
  5. 5.
    Bramwell VHC, Crowther D, O'Malley S, Swindell R, Johnson R, Cooper EH, Thatcher N, Howell A (1985) Activity of JM9 in advanced ovarian cancer: a phase I–II trial. Cancer Treat Rep 69: 409–416Google Scholar
  6. 6.
    Calvert AH, Harland SJ, Newell DR, Siddik ZH, Jones AC, McElwain TJ, Raju S, Wiltshaw E, Smith IE, Baker JM, Peckham MJ, Harrap KR (1982) Early clinical studies withcis-diammine-1,1-cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol 9: 140–147Google Scholar
  7. 7.
    Chary KK, Higby DJ, Henderson ES, Swinerton KD (1977) Phase I study of high dosecis-dichlorodiammine-platinum II with forced diuresis. Cancer Treat Rep 61: 367–370Google Scholar
  8. 8.
    Cleare MJ, Hoeschele JD (1973) Studies on the antitumor activity of group VIII transition metal complexes: I. Platinum (II) complexes. Bioinorg Chem 2: 187–210Google Scholar
  9. 9.
    Cleare MJ, Hydes PC, Malerbi BW, Walkins DM (1978) Antitumor platinum complexes: relationships between chemical properties and activity. Biochimie 60: 835–850Google Scholar
  10. 10.
    Cleare MJ, Hydes PC, Hepburn DR, Malerbi BW (1980) Antitumor platinum complexes: structure-activity relationships. In: Prestayko AW, Crooke ST, Carter SK (eds) Cisplatin-current status and new developments. Academic, New York, pp 149–170Google Scholar
  11. 11.
    Connors TA, Cleare MJ, Harrap KR (1979) Structure-activity relationships of the antitumor platinum coordination complexes. Cancer Treat Rep 63: 1499–1502Google Scholar
  12. 12.
    Corder MP, Elliott TE, Bell SJ (1977) Dose limiting myelotoxicity in absence of significant nephrotoxicity with a weekly out-patient schedule ofcis-platinum (II) diamminedichloride. J Clin Hematol Oncol 7: 645–651Google Scholar
  13. 13.
    Creaven PJ, Madajewicz S, Pendyala L, Mittleman A, Pontes E, Spaulding M, Arbuck S, Solomon J (1983) Phase I clinical trial ofcis-dichloro-trans-dihydroxy-bis-isopropylamine platinum (IV) (CHIP). Cancer Treat Rep 67: 795–800Google Scholar
  14. 14.
    Curt GA, Grygiel JJ, Corden BJ, Ozols RF, Weiss RB, Tell DT, Myers CE, Collins JM (1983) Phase I and pharmacokinetic study of diammine cyclobutane dicarboxylatoplatinum (NSC-241240). Cancer Res 43: 4470–4473Google Scholar
  15. 15.
    Ducore JM, Erickson LC, Zwelling LA, Laurent G, Kohn KW (1982) Comparative studies of DNA cross-linking and cytotoxicity in Burkitt's lymphoma cell lines treated withcis-diamminedichloroplatinum (II) andl-phenylalanine mustard. Cancer Res 42: 897–902Google Scholar
  16. 16.
    Fleiss JL (1981) Statistical methods for rates and proportions. Wiley and Sons, New YorkGoogle Scholar
  17. 17.
    Ginsberg S, Lee F, Issell B, Poiesz B, Rudolph A, Louie A, Bradley E, Tinsley R, DiFino S, Scalzo A, Gullo T, Lerner M, Palmer N, Fitzpatrick A, Comis R (1983) A phase I study ofcis-dichloro-trans-dihydroxy-bis (isopropylamine) platinum IV (CHIP) administered by intravenous bolus daily for 5 days. Proc Am Soc Clin Oncol 2: 35Google Scholar
  18. 18.
    Gormley PE, Bull JM, LeRoy AF, Cysyk R (1979) Kinetics ofcis-dichlorodiammineplatinum. Clin Pharmacol Ther 25: 351–357Google Scholar
  19. 19.
    Gullo JJ, Litterst CL, Maquire PJ, Sikic BI, Hoth DF, Woolley PV (1980) Pharmacokinetics and protein binding ofcis-dichlorodiammine platinum(II) administered as a one hour or as a twenty hour infusion. Cancer Chemother Pharmacol 5: 21–26Google Scholar
  20. 20.
    Harder HC, Rosenberg B (1970) Inhibitory effects of antitumor platinum compounds on DNA, RNA and protein synthesis in mammalian cells in vitro. Int J Cancer 6: 207–216Google Scholar
  21. 21.
    Harland SJ, Newell DR, Siddik ZH, Chadwick R, Calvert AH, Harrap KR (1984) Pharmacokinetics ofcis-diammine-1,1-cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function. Cancer Res 44: 1693–1697Google Scholar
  22. 22.
    Higby DJ, Wallace HJ Jr, Holland JF (1973)cis-Diamminedichloroplatinum (NSC-119875): a phase I study. Cancer Chemother Rep 57:459–463Google Scholar
  23. 23.
    Hill JM, Loeb E, Pardue A, Khon A, King JJ, Aleman C, Hill NO (1979) Platinum analogs of clinical interest. Cancer Treat Rep 63:1509–1513Google Scholar
  24. 24.
    Himmelstein KJ, Patton TF, Beld RJ, Taylor S, Repta AJ, Sternson LA (1981) Clinical kinetics of intact cisplatin and some related species. Clin Pharmacol Ther 29:658–664Google Scholar
  25. 25.
    Joss RA, Kaplan S, Goldhirsh A, Sessa C, Brunner KW, Cavalli F (1984) A phase I trial ofcis-diammine-1, 1-cyclobutane dicarboxylate platinum(II) (Carboplatin, CBDCA, JM-8) with a single dose every five week-schedule. Invest New Drugs 2:297–304Google Scholar
  26. 26.
    Kelman AO, Peresie HJ (1979) Mode of DNA binding of cis-platinum(II) antitumor drugs: a base sequence-dependent mechanism is proposed. Cancer Treat Rep 63:1445–1452Google Scholar
  27. 27.
    Koeller JM, Trump DL, Tutsch KD, Earhart RH, Davis TE, Tormey DC (1986) Phase I clinical trial and pharmacokinetics of carboplatin (NSC-241240) by single monthly 30 minute infusion. Cancer 57:222–225Google Scholar
  28. 28.
    Kreisman H, Ginsburg S, Propert KJ, Richards F, Graziano S, Green M (1987) Carboplatin or iproplatin in advanced non-small cell lung cancer: a Cancer and Leukemia Group B study. Cancer Treat Rep 71:1049–1052Google Scholar
  29. 29.
    Lelieveld P, Van der Vijgh WJF, Veldhuizen RW, Van Velzen D, Van Putten LM, Atassi G, Danguy A (1984) Preclinical studies on toxicity, antitumor activity and pharmacokinetics of cisplatin and three recently developed derivatives. Eur J Cancer Clin Oncol 20:1087–1104Google Scholar
  30. 30.
    Lenaz I, Canetta R, Hilgard P, Florentine S, Bedogni P (1982) The selection of new cisplatin analogs for clinical evaluation. Chemioterapia 1:90–97Google Scholar
  31. 31.
    Leyvraz S, Ohnuma T, Lassus M, Holland J (1985) Phase I study of carboplatin in patients with advanced cancer, intermittent intravenous bolus, and 24-hour infusion. J Clin Oncol 3:1385–1392Google Scholar
  32. 32.
    Lippard SJ (1982) New Chemistry of an old molecule:cis-[Pt(NH3)2]. Science 218:1075–1082Google Scholar
  33. 33.
    Lippman SJ, Helson C, Helson L, and Krakoff IH (1973) Clinical trials ofcis-diamminedichloroplatinum (NSC-119875). Cancer Chemother Rep 57:191–200Google Scholar
  34. 34.
    Loeher PJ, Einhorn LH (1984) Cisplatin. Ann Intern Med 100:704–713Google Scholar
  35. 35.
    Macquet JP, Theophamides T (1975) DNA platinum interactions in vitro withtrans-acis-Pt (NH3)2Cl2. Bioinorg Chem 5: 59–66Google Scholar
  36. 36.
    Mallard MM, Macquet JP, Theophamides T (1975) X-ray photoelectron spectroscopy of DNA Pt complexes. Evidence of O6(Gua)N7(Gua) chelation of DNA withcis-chlorodiammineplatinum(II). Biochim Biophys Acta 402:166–170Google Scholar
  37. 37.
    Mansy S, Rosenberg B, Thompson AJ (1973) Binding ofcis- andtrans-dichlorodiammineplatinum(II) to nucleosides: I. Location of the binding sites. J Am Chem Soc 95:1633–1640Google Scholar
  38. 38.
    McGuire W, Blessing J, Stehman F, Hatch K (1985) Phase II study of CHIP in advanced squamous cell carcinoma of the cervix. Proc Am Soc Clin Oncol 4:121Google Scholar
  39. 39.
    McGuire WP, Arseneau JC, Blessing JA, Given FT, Hatch KD, Creasman WT, di Saia PJ, Teng NN (1988) Randomized comparison of carboplatin (CP) and iproplatin (IP) in advanced squamous carcinoma of the uterine cervix (SCUC): a Gynecologic Oncology Group (GOG) study. Proc Am Soc Clin Oncol 7:135Google Scholar
  40. 40.
    Mong S, Huang CH, Prestayko AW, Crooke ST (1980) Effects of second-generation platinum analogs on isolated PM-2 DNA and their cytotoxicity in vitro and in vivo. Cancer Res 40:3318–3324Google Scholar
  41. 41.
    Pascoe JM, Roberts JJ (1974) Interactions between mammalian cell DNA and inorganic platinum compounds — I. Biochem Pharmacol 23:1345–1357Google Scholar
  42. 42.
    Pascoe JM, Roberts JJ (1974) Interactions between mammalian cell DNA and inorganic platinum compounds — II. Biochem Pharmacol 23:1359–1366Google Scholar
  43. 43.
    Penyala L, Greco W, Cowens JW, Madajewicz S, Creaven PJ (1983) Pharmacokinetics ofcis-dichloro-trans-dihydroxy-bisisopropylamine platinum IV (CHIP) in patients with advanced cancer. Cancer Chemother Pharmacol 11:23–28Google Scholar
  44. 44.
    Peyrot V, Briand C, Braguer CO, Chellvet-Monges AM, Sari JC (1983) Action of hydrolyzed cisplatin and some analogs on microtubule protein polymerization in vitro. Cancer Treat Rep 67:641–646Google Scholar
  45. 45.
    Prestayko AW, Bradner WT, Huftalen JB, Rose WG, Schurig JE, Cleare MJ, Hayes PC, Crooke ST (1979) Antileukemic (L1210) activity and toxicity ofcis-dichlorodiammineplatinum(II) analogs. Cancer Treat Rep 63:1503–1508Google Scholar
  46. 46.
    Priego V, Luc V, Bonnem E, Rahman A, Smith F, Schein P, Woolley P (1983) A phase I study of pharmacology of diammine-(1,1)-cyclobutane dicarboxlato-(2-1-0)-platinum (CBDCA) administered on a weekly schedule. Proc Am Soc Clin Oncol 2:30Google Scholar
  47. 47.
    Ribaud P, Goveia J, Dorval T, Misset JL, Machover D, Gastiaburu J, Schwarzenberg L, Mathe G (1984) Phase I study of CHIP. Invest New Drugs 2 (1):103Google Scholar
  48. 48.
    Roberts JJ, Pasco JM (1972) Cross-linking of complementary strands of DNA in mammalian cells by antitumor platinum compounds (letter). Nature 235:282–284Google Scholar
  49. 49.
    Rose WC, Bradner WT (1984) Experimental antitumor activity of platinum coordination complexes. In: Hacher MP, Douple EB, Krakoff IH (eds) Platinum coordination complexes in cancer chemotherapy. Martin Nijhoff, Boston, pp 228–239Google Scholar
  50. 50.
    Rose WC, Schurig JE, Huftalen JB, Bradner WT (1982) Antitumor activity and toxicity of cisplatin analogs. Cancer Treat Rep 66:135–146Google Scholar
  51. 51.
    Rosenberg B (1979) Anticancer activity ofcis-dichlorodiammine-platinum(II) and some relevant chemistry. Cancer Treat Rep 63:1433–1438Google Scholar
  52. 52.
    Rosenberg B, Van Camp L, Trosko JE, Mansour VH (1969) Platinum compounds: a new class of potent antitumor agents. Nature 222:385–386Google Scholar
  53. 53.
    Rossof AH, Slayton ER, Perlia CP (1972) Preliminary clinical experience withcis-diamminedichloroplatinum(II) (NSC-119875, CACP). Cancer 30:1451–1456Google Scholar
  54. 54.
    Royer-Pokora B, Gordon LK, Haseltine WA (1981) Use of exonuclease III to determine the site of stable lesions in defined sequences of DNA: the cyclobutane pyrimidine dimer andcis- andtrans-dichlorodiammine platinum II examples. Nucleic Acids Res 9:4595–4609Google Scholar
  55. 55.
    Rozencweig M, Nicaise C, Beer M, Crespeigne N, Van Rijmenant M, Lenaz L, Kenis Y (1983) Phase I study of carboplatin given on a five-day intravenous schedule. J Clin Oncol 1:621–626Google Scholar
  56. 56.
    Simon R, Wittes RE, Ellenberg SE (1985) Randomized phase II clinical trials. Cancer Treat Rep 69:1375–1381Google Scholar
  57. 57.
    Talley RW, O'Bryan RM, Gutterman JU, Brownlee RW, McCredie E (1973) Clinical evaluation of toxic effects ofcis-diamminedichloroplatinum (NSC-119875) — phase I clinical study. Cancer Chemother Rep 57:465–471Google Scholar
  58. 58.
    U. S. Departement of National Technical Information Services Reports: PB 84163740 “A toxicologic evaluation of five platinum-containing compounds: NSC-119875, NSC-224964, NSC-241240, NSC-250427, and NSC-256927 in dogs.” (MRI-KC-PT-3899-79-19); PB 84 163757 “Amendment to Report MRI-KC-PT-3899-79-19. ‘A toxicological evaluation of five platinum-containing compounds: NSC-119875, NSC-224964, NSC-241240, and NSC-256927 in dogs.‘“ (MRI-KC-PT-3899-81-29); PB 82 165028 “Preclinical toxicologic evaluation of diammine [1,1-cyclobutanedi-carboxylato(2-)O,O']-(SP-4-2) platinum (NSC-241240) given intravenously to mice.” (MRI-KC-PT-7150-81-1); PB 297710/AS “Renal toxicity study of NSC 241240 and NSC-271674.” (IITRI-Tox-241240/271674-78-15); PB 288368/AS “Renal toxicity study of NSC-250427 and NSC-256927 in the rat.” (IITRI-Tox-250427/256927-78-14)Google Scholar
  59. 59.
    Van Echo DA, Egorin MJ, Whitacre MY, Olman EA, Aisner J (1984) Phase I and pharmacologic trial of carboplatin daily for 5 days. Cancer Treat Rep 68:1103–1114Google Scholar
  60. 60.
    Wolpert-DeFillipes MK (1979) Antitumor activity ofcis-dichlorodiammine-platinum(II). Cancer Treat Rep 63:1453–1458Google Scholar
  61. 61.
    Wolpert-DeFillipes MK (1980) Antitumor activity of cisplatin analogs. In: Prestayko AW, Crooke ST, Carter SK (eds) Cisplatin-current status and new developments. Academic, New York, pp 183–191Google Scholar
  62. 62.
    Zwelling LA, Kohn KW (1979) Mechanism of action ofcis-dichlorodiammine-platinum(II). Cancer Treat Rep 63:1439–1444Google Scholar
  63. 63.
    Zwelling LA, Kohn KW, Ross WE, Ewig RAG, Anderson T (1978) Kinetics of formation and disappearance of a DNA cross-linking effect in mouse leukemia L1210 cells treated withcis- andtrans-diamminedichloroplatinum(II)Google Scholar
  64. 64.
    Zwelling LA, Anderson T, Kohn KW (1979) DNA protein and DNA interstrand cross-linking bycis- andtrans-platinum(II)diamminedichloride in L1210 mouse leukemia cells and relation to cytotoxicity. Cancer Res 39:365–369Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • Brenda J. Foster
    • 1
  • Bonnie J. Harding
    • 1
  • Mary K. Wolpert-DeFilippes
    • 2
  • Lawrence Y. Rubinstein
    • 3
  • Kathleen Clagett-Carr
    • 1
  • Brian Leyland-Jones
    • 1
  1. 1.Cancer Therapy Evaluation Program, Investigational Drug BranchNational Cancer InstituteBethesdaUSA
  2. 2.Developmental Therapeutics ProgramNational Cancer InstituteBethesdaUSA
  3. 3.Biometric Research BranchNational Cancer InstituteBethesdaUSA

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