COLLATERAL SENSITIVITY OF 6-MERCAPTOPURINE-RESISTANT SUBLINES OF P388-LEUKEMIA AND L1210-LEUKEMIA TO THE NEW PURINE ANTAGONISTS, 5-CARBAMOYL-H-1-IMIDAZOL-4-YL PIPERONYLATE AND 4-CARBAMOYLIMIDAZOLIUM 5-OLATE

  • 1 January 1982
    • journal article
    • research article
    • Vol. 42  (3) , 1103-1106
Abstract
Two new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250) and 4-carbamoylimidazolium 5-olate (SM-108), were investigated for their antitumor activities against 6-mercaptopurine (6-MP)-resistant sublines of P388 and L1210 leukemia [mouse cell lines]. Both resistant sublines exhibited collateral sensitivity instead of cross-resistance to these new antipurine drugs. Since more potent cytotoxic activities of these drugs against 6-MP-resistant cells were observed even in in vitro cell culture systems, this collateral sensitivity was proved on a cellular basis. Biochemical studies revealed that 6-MP-resistant sublines of P388 and L1210 leukemia are deficient in hypoxanthine-guanine phosphoribosyltransferase activity. In these cells, not only the activation of 6-MP to its nucleotide but also the synthesis of GMP via the salvage pathway seems to be severely restricted. However, SL-1250 and SM-108 can be activated to their nucleotide even in these 6-MP-resistant cells because the activation of these compounds is proceeded by adenine phosphoribosyltransferase. Suppression of de novo purine synthesis with SL-1250 and SM-108 seems to be a very efficient means of killing these 6-MP-resistant cells, which lack a salvage pathway for GMP.