Advances in platinum cancer chemotherapy

Abstract

In the past 4 years substantial progress has been made in the development of platinum cancer chemotherapy. A number of drug candidates have undergone clinical trials and one 'second generation' platinum drug, carboplatin, has been approved for use in the treatment of ovarian and small cell lung cancer. This review covers the major developments since the last international conference on Platinum Chemotherapy in Vermont, and attempts to highlight the primary factors that appear to be influencing the synthesis and screening of potential third generation platinum drugs. A predominant feature in the evaluation of analogues has been the emphasis on chelating diamine complexes, in particular those of diaminocyclohexane, which show activity in L1210 tumours that are resistant to cisplatin, and the use of a wide range of carboxylate ligands as a means of circumventing solubility and toxicity problems inherent in the parent compounds. There has also been an increased effort in studies relating to complexes containing mixed amines and functionalised amines, building on the assumption, which remains valid to date, that two amines are a necessary requirement for anti-tumour activity. Efforts have also been made to address the use of complexes containing biologically active ligands, and the concept of targeting compounds to specific organs and formulating drugs to achieve more specific activity or controlled release of drugs with lower toxicities. These may provide a viable route to drugs that can be administered more easily, for example by an oral route, or show a different spectrum of activity. However, it may prove difficult to adequately characterise these more complex systems. The major problem encountered in evaluating cisplatin analogues, as with other prospective cancer drugs, is finding reproducible anti-tumour screens that are predictive of the behaviour of the drugs in the clinic. Progress is being made in the development of sensitive and resistant human tumour xenograft lines and this area should be monitored with interest, as it may provide a key to the development of a future platinum drug, hopefully with a wider range of activity than either cisplatin or carboplatin.

Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum

“…1) the two amine ligands again are tightly bound, and the two carboxylato ligands function as the leaving groups. Salient topics of platinum drug research, including second-generation compounds, have been reviewed, both very early in the game [5][6][7][8][9][10][11] and in more recent years [12][13][14][15][16][17][18][19][20].…”

A Novel Approach to Preparing Water Soluble Prodrug Forms of Cisplatin Analogues Bearing Chelating Diamines

“…100 MHz 13C NMR (DMFd7): b (re1 intensity) = 45. 4 RP-HPLC Analysis-The basic system consisted of two Altex llOA pumps, an Altex 420 microprocessor controller (Beckman, Fullerton, CA), and a 7125 sample injector (Rheodyne, Contati, CA), which was fitted with a 500 yL injection loop. A 0.4 x 25 cm Nucleosil-100 RP-18 column with a 0.4 x 3.0 cm precolumn (Macherey-Nagel, Duren, Germany) was used for chromatography.…”

Hydrophilic analogs of (R,R)-diaminocyclohexane dichloroplatinum (DACH) and the influence of relative stereochemistry on antitumor activity

“…In spite of the multitude of structural analogs of the antitumor agent cis-diamine dichloroplatinum(II) (cisplatin) (1) only a few are presently used in clinical practice (2). Of these, trans-1,2-diaminocyclohexane dichloroplatinum(1l) (DACH) and its variants with different anionic counterparts appear to be the most effective (3) (Fig.…”