REVERSAL OF RADIATION-INDUCED CISPLATIN RESISTANCE IN MURINE FIBROSARCOMA CELLS BY SELECTIVE MODULATION OF THE CYCLIC GMP-DEPENDENT TRANSDUCTION PATHWAY

Cisplatin resistance, induced in murine fibrosarcoma cells (SSK) in vi tro or in vivo by low-dose irradiation, can be overcome by activation of the cyclic GMP(cGMP)-dependent transduction pathway. This is mediat ed either by stimulating cGMP formation with sodium nitroprusside or b y replacing cGMP with a selective activator of the cGMP-dependent prot ein kinase, 8-bromo-cGMP. The cyclic AMP-dependent transduction pathwa y is not involved in cisplatin resistance. Instead, activation of cAMP sensitises both parental and resistant SSK cells equally to the actio n of cisplatin. There is a 1.8 to 2.5-fold increase in drug toxicity, depending on the activating agent. Enhancement of cisplatin sensitivit y is induced by specific inhibition of cAMP hydrolysis, increase in cA MP formation or by increasing the activation potential to cAMP-depende nt protein kinase by specific cAMP analogues. Cells that have lost cis platin resistance respond to cGMP- or cAMP-elevating agents in the sam e way as the parental SSK cells. The radiation sensitivity is unchange d in all cell lines, even after activation of cAMP or cGMP. These resu lts suggest that specific DNA repair pathways are altered by radiation but affected only in cisplatin damage repair, which is regulated by c GMP. Although there is ample cooperativity and interaction between the cAMP- and the cGMP-dependent transduction pathways, specific substrat e binding by cGMP appears to play an important role in radiation-induc ed cisplatin resistance.