Current status of platinum-based antitumor drugs.

Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual nations. During this time there have been more failures than successes with the development of 14 drugs being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial (satraplatin, picoplatin, Lipoplatin™ and ProLindac™). No new small molecule platinum drug has entered clinical trials since 1999 which is representative of a shift in focus away from drug design and towards drug delivery in the last decade. In this perspective article we update the status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials, and discuss the results in the context of where we believe the field will develop over the next decade.

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The status of platinum anticancer drugs in the clinic and in clinical trials.

Clinical development of platinum complexes in cancer therapy: an historical perspective and an update

The mortality rates from various tumor types can be reduced dramatically by use of highly active drugs. This is particularly true for platinum-based drugs, being among the most effective antineoplastic agents for a number of malignancies (e.g., testicular, ovarian, head and neck, and bladder cancers). Platinum coordination compounds have been successfully applied in cancer chemotherapy for more than 25 years since the introduction of the parent compound for this class of antitumor agents, namely, cis-[diamminedichloroplatinum(II)] (1) known as cisplatin 1 (for structural formula, see Figure 1). Over these decades, a great deal of effort has been devoted to synthesis and testing of the tumor-inhibiting profiles for new metal complexes, with the major impetus toward development and implementation of novel anticancer drugs. These are anticipated to have superior efficacy, increased selectivity for tumor tissue, reduced toxicity, a wider spectrum of activity, lack of tumor cell resistance, and improved pharmacological characteristics (e.g., possibility of oral administration) as compared to cisplatin. Still, of thousands of tested compounds, only a fraction (about 30) have entered clinical trials and merely three Pt drugs have eventually been approved worldwide. 2,3

Interactions of antitumor metallodrugs with serum proteins: advances in characterization using modern analytical methodology.

Thirty years after the onset of the first clinical studies with cisplatin, the development of antineoplastic platinum drugs continues to be a productive field of research. This article reviews the current preclinical and clinical status, including a discussion of the molecular basis for the activity of the parent drug cisplatin and platinum drugs of the second and third generation, in particular their interaction with DNA. Further emphasis is laid on the development of third generation platinum drugs with activity in cisplatin-resistant tumours, particularly on chelates containing 1,2-diaminocyclohexane (DACH) and on the promising and more recently evolving field of non-classic (trans- and multinuclear) platinum complexes. The development of oral platinum drugs and drug targeting strategies using liposomes, polymers or low-molecular-weight carriers in order to improve the therapeutic index of platinum chemotherapy are also covered.

Tumour-inhibiting platinum complexes--state of the art and future perspectives.

In phase I studies, lobaplatin showed activity in ovarian cancer patients pretreated with platinum. A phase II trial with lobaplatin was performed in patients with refractory or relapsed ovarian cancer to define activity and pharmacokinetics. Twenty-two patients were treated with lobaplatin administered as an intravenous bolus every 4 weeks. Dependent on creatinine clearance (CRCL) patients received 30 or 50 mg m-2 lobaplatin as the starting dose. Twenty-two patients received 78 courses (median 3, range 1-6). In eight patients total platinum (TPt) in plasma and urine, free platinum (FPt) in plasma ultrafiltrate (both measured by atomic absorption spectrometry) and lobaplatin in plasma ultrafiltrate measured (by high-performance liquid chromatography) were measured. Toxicity was confined to mild nausea and vomiting, mild leucocytopenia (WHO grade 3 in 18% of the courses), and renal function-related thrombocytopenia (WHO grade 3/4 in 53% of the courses). A correlation was found between CRCL and reduction in platelet count (r = -0.77; P < 0.01). No renal toxicity was encountered. Five of 21 evaluable patients (24%) achieved a response (four complete remissions and one partial remission). Remissions occurred mainly in patients who relapsed more than 6 months after primary treatment. The median survival from start of lobaplatin treatment was 8 months. The mean areas under the curve (AUCs) were 4.2 +/- 0.5, 3.0 +/- 0.6, and 3.2 +/- 1.1 h mgl-1 for TPt, FPt and lobaplatin respectively. The free platinum fraction (FPt/TPt) was initially very high, indicating low protein binding. FPt was essentially present as intact lobaplatin. Four hours after infusion 54 +/- 5% and 24 h after infusion 74 +/- 3% of the lobaplatin dose was excreted in the urine. In conclusion, lobaplatin is a platinum compound with anti-tumour activity in patients with relapsed ovarian cancer, especially in those who have platinum-sensitive tumours. The main toxicity of lobaplatin is thrombocytopenia and its dose should be corrected according to renal function.

Phase-ii and pharmacokinetic study of lobaplatin in patients with relapsed ovarian-cancer

Chemotherapy dose-escalation with hematopoietic growth-factor support in ovarian-cancer

Fifty-three patients with histologically proven ovarian cancer were treated with intraperitoneally administered cisplatin or human recombinant interferon-alpha through a totally implanted peritoneal access port. A total of 281 treatment courses were given. No complications related to surgical implantation of the port were seen. Infectious complications, intra-abdominal problems or subcutaneous drug extravasation did not occur. In two patients the number of treatment courses was limited due to inflow obstruction. A totally implanted peritoneal access port proves to be a reliable route for the intraperitoneal treatment of patients with ovarian cancer. The strict aseptic technique we used contributes to its safety by preventing intra-abdominal infections.

https://ijgc.bmj.com/content/ijgc/2/2/107.full.pdf

J. Boonstra

Papers

Phase-ii and pharmacokinetic study of lobaplatin in patients with relapsed ovarian-cancer

Chemotherapy dose-escalation with hematopoietic growth-factor support in ovarian-cancer

Low complication rate during intraperitoneal therapy through a totally implanted peritoneal access port in patients with ovarian-cancer