Abstract
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.
Highlights
DNA level, such as DNA repair inhibitors and chromatin conformation modulators will be discussed
Modulation of accumulation has been achieved by treatments that are thought to have membrane fluidising effects, such as hyperthermia as well as with drugs that can be grouped as membrane active and signal transduction modulators (Table II)
Forskolin increased CDDP accumulation only in the sensitive cells. This correlated with a more pronounced effect on cytotoxicity in sensitive compared with resistant cells. These findings suggest a role for cyclic adenosine monophosphate (cAMP) activated signal transduction, at least in ovarian carcinoma cell lines, in CDDP efficacy and a possible route for modulation through this system
Summary
In many CDDP resistant cell lines reduced CDDP accumulation was observed (for reviews: Andrews & Howell, 1990; de Graeff et al, 1988; Hospers et al, 1988b; Kelley & Rozencweig, 1989). For two CDDP resistant human ovarian carcinoma cell lines, with reduced cellular CDDP, accumulation related changes in the potentials of plasma- (A2780-CP) or mitochondrial- (2008/Cl3*) membranes were described (Andrews & Albright, 1991). In 2008/DDP cells a decreased number of Na+,K+-adenosine triphosphatase molecules/mg protein was found an indication for a role of Na+,K+adenosine triphosphatase in CDDP accumulation and resistance (Andrews et al, 1991). On the other hand the increased expression of a 200kD membrane glycoprotein in CDDP resistant murine thymic lymphoma cells (Kawai et al, 1990) coinciding with a decreased CDDP accumulation was reported. No direct proof for the role of this protein as a carrier is available
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