Modulation of cis-diamminedichloroplatinum(II) resistance: a review

Abstract

Summary In this review an inventory is made of agents used to circumvent cis-diamminedichloroplatinum(II) (CDDP) resistance in vitro and in vivo. Agents that affect CDDP accumulation and membrane related systems, cytoplasmic defense mechanisms, as well as DNA accessibility and repair are reviewed.In resistant cell lines that have decreased accumulation, this can be restored by hyperthermic treatment. With or without effects on accumulation compounds that affect cell signal transduction often increase CDDP cytotoxicity. Calcium channel blockers and calmodulin inhibitors do not seem to be uniformly good modulators of CDDP resistance. For transduction modulators as well as cellular calcium affecting agents mechanisms are mainly unclear or controversial. Glutathione appears, with the now available agents, to be the most promising target for modulation of cytoplasmic defense mechanisms. At the nuclear level the inhibition of DNA repair related enzymes as well as the use of modified nucleosides to interfere with repair is studied in various cell lines. Results with these agents suggest opportunities for clinically feasible cytotoxicity modulation. DNA accessibility could in vitro be affected, but seems to be an unreliable target for modulation. Whenever possible the resistance mechanism affected and the mode of action of the modulator are discussed. As an alternative for modulation another method of overcoming CDDP resistance namely the application of CDDP analogues is considered.

Mechanisms of cell uptake and toxicity of the anticancer drug cisplatin

“…One is the development of tumour resistance to the drug during therapy, leading to treatment failure. [4][5][6][7] The other is the drug's nephrotoxicity, which limits the dose that can be administered. 8 It is clear that much remains to be understood about the biophysical interactions of cisplatin with the cell membrane and with membrane-bound proteins.…”

“…However, from experiments with cell lines to which cisplatin was administered at concentrations above the normal pharmacological level, a number of factors have been identified as contributing to resistance. [4][5][6][7] At this stage, important mechanisms responsible for the development of cisplatin resistance appear likely to be: (1) decreased cytoplasmic accumulation of cisplatin, (2) increased levels of glutathione or glutathione-S-transferase activity, (3) increased levels of cytoplasmic metallothioneins, and (4) enhanced DNA repair. Here we will concentrate on the first of these possible mechanisms, i.e., decreased cytoplasmic accumulation of the drug.…”

Codominance of cisplatin resistance in somatic cell hybrids

“…However, the presence of intrinsic or acquired resistance to cisplatin in cancer cells remains a major obstacle to successful cancer chemotherapy. Resistance to cisplatin in cultured cancer cells has been studied extensively and found to be multifactorial with drug accumulation defects (Eastman et al, 1986;Richon et al, 1987;Shen et al, 2000), increased detoxification mediated by glutathione or metallothionein (Moscow and Cowan, 1988;Kasahra et al, 1991;Shellard et al, 1991;Timmer-Bosscha et al, 1992), alterations of cell cycle regulators and signal transduction pathways (Basu et al, 1996;Kondo et al, 1996;Liu et al, 1996;Ruan et al, 1998), and increased repair of DNA damage (Barnes et al, 1993;Chu, 1994;Lai et al, 1995;Johnson et al, 1996;Fink et al, 1998). However, the exact mechanisms of cisplatin resistance require further elucidation.…”

Reversal of Cisplatin Resistance by the 1,4‐Benzothiazepine Derivative, JTV‐519

“…1) Some agents reversing cisplatin resistance have been developed. 8) We have previously reported that amphotericin B reversed cisplatin resistance.…”