Skip to main content
SpringerLink
Log in

New Developments and Approaches in the Platinum Arena

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Following the introduction of cisplatin and the demonstration of its importance in the treatment of testicular and ovarian cancer, there was a need to develop less toxic analogues. Compared with cisplatin, carboplatin proved markedly less toxic to the kidneys and nervous system and caused less nausea and vomiting, while generally (and certainly for ovarian cancer) retaining equivalent antitumour activity. In many situations, carboplatin is now the drug of choice in view of the improved quality of life it offers patients.

Many drug combinations involving platinum complexes have been explored, but those with taxanes are particularly noteworthy. Paclitaxel in combination with a platinum agent is now accepted as a standard component of first-line treatment for ovarian cancer, and produces improved survival.

Preclinical studies suggested that drugs containing the diaminocyclohexane ligand would be capable of overcoming intrinsic or acquired resistance. However, this outcome was not realised in the clinic until the development of oxaliplatin, which appears to have a different spectrum of activity compared with cisplatin and carboplatin. Oxaliplatin improves the response rate and progression-free survival when given with fluorouracil for the treatment of advanced colorectal cancer, and its activity in other tumour types is under investigation.

ZD0473 is a platinum analogue that relies on steric hindrance to overcome thiolmediated detoxification. It has a good tolerability profile, is currently undergoing phase II testing, and its activity in combination with other agents is being explored.

The trinuclear platinum complex BBR3464 also looks promising in preclinical studies and will shortly be evaluated in phase II trials.

Although much research remains to be done, these new developments in platinum-based chemotherapy should translate into significant improvements in treatment for patients with a broad range of tumour types.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Wiltshaw E, Carr B. Cis-platinum(II)diammine-dichloride. In: Connors TA, Roberts JJ, editors. Platinum coordination complexes in cancer chemotherapy. Heidelberg: Springer-Verlag, 1974: 178–82

    Chapter  Google Scholar 

  2. Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 1999; 17: 409–22

    PubMed  CAS  Google Scholar 

  3. Aabo K, Adnitt P, Adams M, et al. Chemotherapy in advanced ovarian cancer: an overview of randomized clinical trials. BMJ 1991; 303: 884–93

    Article  Google Scholar 

  4. Kelland LR. Preclinical perspectives on platinum resistance. Drugs 2000; 59 Suppl. 4: 1–8

    Article  PubMed  CAS  Google Scholar 

  5. Rowinsky EK, Donehower RC. The clinical pharmacology of paclitaxel (TAXOL). Semin Oncol 1992; 20 Suppl. 3: 16–25

    Google Scholar 

  6. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334: 1–6

    Article  PubMed  CAS  Google Scholar 

  7. Stuart G, Bertelsen K, Mangioni C, et al. Updated analysis shows a highly significant improved overall survival (OS) for cisplatin-paclitaxel as first line treatment of advanced ovarian cancer: mature results of the EORTC-GCCG, NO-COVA, NCIC CTG and Scottish Intergroup Trial [abstract 1394]. Proc Am Soc Clin Oncol 1998; 17

  8. Adams M, Calvert AH, Carmichael J, et al. Chemotherapy for ovarian cancer —a consensus statement on standard practice. Br J Cancer 1998; 78: 1404–6

    Article  PubMed  CAS  Google Scholar 

  9. duBois A, NitzU, Schroder W, et al. Cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line chemotherapy in ovarian cancer: interim analysis of an AGO Study Group trial [abstract 1272]. 33rd Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, 357a

  10. Neijt JP, Hansen M, Hansen SW, et al. Randomized phase III study in previously untreated epithelial ovarian cancer FIGO stage TIB, IIC, III, IV, comparing paclitaxel-cisplatin and paclitaxel-carboplatin [abstract 1259]. 33rd Annual Meeting, American Society of Clinical Oncology; 1997 May 17–20; Denver, 352a

  11. McGuire WP, Ozols RF. Chemotherapy of advanced ovarian cancer. Semin Oncol 1998; 25: 340–8

    PubMed  CAS  Google Scholar 

  12. Vaughn DJ, Malkowicz SB, Zoltick B, et al. Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: an active and tolerable outpatient regimen. J Clin Oncol 1998; 16: 255–60

    PubMed  CAS  Google Scholar 

  13. Vasuratna A, Kudelka AP, Edwards CL, et al. Prolonged remission of endometrial cancer wth paclitaxel and carboplatin. Anticancer Drugs 1998; 9: 283–5

    Article  PubMed  CAS  Google Scholar 

  14. Mangioni C, Landoni F, Colombo A, et al. Concurrent platinum-based chemo-and radiotherapy for locally advanced cervical cancer: a new gold-standard treatment? Ann Oncol 1999; 10(6): 647–8

    Article  PubMed  CAS  Google Scholar 

  15. National Cancer Institute. Clinical announcement: concurrent chemoradiation for cervical cancer [online]. National Cancer Institute, 2000 Feb 24. Available from: URL: http://cancertrials.nci.nih.gov/types/cervical/announcement/index.html [Accessed 2000 Mar 27]

  16. Burchenal JH, Iranai G, Kern K,et al. 1,2-Diaminocyclohexane platinum derivatives of potential clinical value. Recent Results Cancer Res 1980; 74: 146–55

    Article  PubMed  CAS  Google Scholar 

  17. Figg WD, Christian MC, Lush R, et al. Pharmacokinetics of elemental platinum (ultrafiltrate and total) after a thirty minute intravenous infusion of ormaplatin. Biopharm Drug Dispos 1997; 18: 347–59

    Article  PubMed  CAS  Google Scholar 

  18. O'Rourke TJ, Weiss RB, New P, et al. Phase I clinical trial of ormaplatin (tetraplatin, NSC 363812). Anticancer Drugs 1994; 5: 520–6

    Article  PubMed  Google Scholar 

  19. Rixe O, Ortuzar W, Alvarez M, et al. Oxaliplatin, tetraplatin, cisplatin and carboplatin: spectrum of activity in drug-resistant cell lines and in cell lines of the National Cancer Institute's Anticancer Drug Screen Panel. Biochem Pharmacol 1996; 52: 1855–65

    Article  PubMed  CAS  Google Scholar 

  20. Becouarn Y, Ychou M, Ducreux M, et al. Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 1998; 16: 2739–44

    CAS  Google Scholar 

  21. Levi FA, Zidani R, Vannetzel J-M, et al. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. J Natl Cancer Inst USA 1994; 86: 1608–17

    Article  CAS  Google Scholar 

  22. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000; 18: 136–47

    PubMed  CAS  Google Scholar 

  23. de Gramont A, Figer A, Seymour M, et al. A randomized trial of leucovorin (LV) and 5-fluorouracil (5FU) with or without oxaliplatin in advanced colorectal cancer (CRC) [abstract no. 985]. Proc Am Soc Clin Oncol 1998; 17: 257a

    Google Scholar 

  24. Machover D, Diaz-Rubio E, Gramont A, et al. Two consecutive phase II trials of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 1996; 7: 95–8

    Article  PubMed  CAS  Google Scholar 

  25. Raymond E, Chaney SG, Taamma A, et al. Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 1998; 9(10): 1053–71

    Article  PubMed  CAS  Google Scholar 

  26. Kelland LR, Jones M, Abel G, et al. Human ovarian carcinoma cell lines and companion xenografts: a disease oriented approach to new platinum anticancer drug development. Cancer Chemother Pharmacol 1992; 30: 43–50

    Article  PubMed  CAS  Google Scholar 

  27. Mistry P, Kelland LR, 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: 215–20

    Article  PubMed  CAS  Google Scholar 

  28. Holford J, Raynaud F, Murrer BA, et al. Chemical, biochemical and pharmacological activity of the novel sterically hindered platinum co-ordination complex cis-[amminedichloro(2-methylpyridine)] platinum (II) (AMD473). Anticancer Drug Des 1998; 13: 1–8

    PubMed  CAS  Google Scholar 

  29. Holford J, Sharp SY, Murrer BA, et al. In vitro circumvention of cisplatin resistance by the novel sterically hindered platinum complex AMD473. Br J Cancer 1998; 77: 366–73

    Article  PubMed  CAS  Google Scholar 

  30. Kelland LR, Sharp SY, O'Neill CF, et al. Discovery and development of platinum complexes designed to circumvent cisplatin resistance. J Inorg Biochem 1999; 77: 111–5

    Article  PubMed  CAS  Google Scholar 

  31. Raynaud FI, Boxall FE, Goddard PM, et al. Cisamminedichloro (2-methylpyridine) platinum (II) (AMD473), a novel sterically hindered platinum complex: In vivo activity, toxicology, and pharmacokinetics in mice. Clin Cancer Res 1997; 3: 2063–74

    PubMed  CAS  Google Scholar 

  32. Trigo JM, Beale P, Judson IR, et al. Phase I and pharmacokinetic (PK) study of Cis-amminedichloro(2-methylpyridine) platinum (II) (ZD0473), a novel sterically hindered platinum complex, in patients (pts) with advanced solid malignancies [abstract no. 648m]. 35th Annual Meeting, American Society of Clinical Oncology; 1999 May 15–18; Atlanta, 169a

  33. Pratesi G, Perego P, Polizzi D, et al. A novel charged trinuclear platinum complex effective against cisplatin-resistant tumours: hypersensitivity of p53-mutant human tumour xenografts. Br J Cancer 1999; 80: 1912–9

    Article  PubMed  CAS  Google Scholar 

  34. Brabec V, Kasparkova J, Vrana O, et al. DNA modifications by a novel bifunctional trinuclear platinum phase I anticancer agent. Biochemistry 1999; 38: 6781–90

    Article  PubMed  CAS  Google Scholar 

  35. Manzotti C, Pratesi G, Menta E, et al. BBR3464: a novel triplatinum complex, exhibiting a preclinical profile of antitumor efficacy different from cisplatin. Clin Cancer Res. In press

  36. Perego P, Caserini C, Gatti L, et al. A novel trinuclear platinum complex overcomes cisplatin resistance in an osteosarcoma cell system. Mol Pharmacol 1999; 55: 528–34

    PubMed  CAS  Google Scholar 

  37. Calvert PM, Highley MS, Hughes AN, et al. A phase I study of a novel, trinuclear, platinum analogue, BBR3464, in patients with advanced solid tumors [abstract/poster no. 333]. Clin Cancer Res 1999; 5

  38. Sessa C, Capri G, Gianni L, et al. A phase I with accelerated titration design (ATD) and pharmacokinetic (PK) study of BBR3464, a novel cationic triplatinum complex [abstract 613]. Clin Cancer Res 1999; 5

  39. Akaza H, Togashi M, Nishio Y, et al. Phase II study of cisdiammine (glycolato)platinum, 254-S, in patients with advanced germ-cell testicular cancer, prostatic cancer, and transitional-cell carcinoma of the urinary tract. Cancer Chemother Pharmacol 1992; 31: 187–92

    Article  PubMed  CAS  Google Scholar 

  40. Judson I, Cerny T, Epelbaum R, et al. Phase II trial of the oral platinum complex JM216 in non-small-cell lung cancer: an EORTC early clinical studies group investigation. Ann Oncol 1997; 8(6): 604–6

    Article  PubMed  CAS  Google Scholar 

  41. Kelland LR, Abel G, McKeage MJ, et al. Preclinical antitumor evaluation of Bis-acetato-ammine-dichloro cyclohexylamine platinum (IV): an orally active platinum drug. Cancer Res 1993; 53: 2581–6

    PubMed  CAS  Google Scholar 

  42. McKeage MJ, Raynaud F, Ward J, et al. Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer. J Clin Oncol 1997; 15: 2691–700

    PubMed  CAS  Google Scholar 

  43. McKeage MJ, Mistry P, Ward J, et al. Aphase I and pharmacology study of an oral platinum complex, JM216: dose-dependent pharmacokinetics with single dose administration. Cancer Chemother Pharmacol 1995; 36(6): 451–8

    Article  PubMed  CAS  Google Scholar 

  44. Beale P, Raynaud F, Hanwell J, et al. Phase I study of oral JM216 given twice daily. Cancer Chemother Pharmacol 1998; 42(2): 142–8

    Article  PubMed  CAS  Google Scholar 

  45. Newman MS, Colbern GT, Working PK, et al. Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice. Cancer Chemother Pharmacol 1999; 43: 1–7

    Article  PubMed  CAS  Google Scholar 

  46. Kelland LR, Barnard CFJ, Mellish KJ, et al. A novel trans-platinum coordination complex possessing in vitro and in vivo antitumor activity. Cancer Res 1994; 54: 5618–22

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, England

    Ian Judson & Lloyd R. Kelland

Authors
  1. Ian Judson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lloyd R. Kelland
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Judson, I., Kelland, L.R. New Developments and Approaches in the Platinum Arena. Drugs 59 (Suppl 4), 29–36 (2000). https://doi.org/10.2165/00003495-200059004-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200059004-00004

Keywords

Search

Navigation