title: 9-Deazaadenosine--a new potent antitumor agent.
abstract: -Deazaadenosine (9-DAA), a novel purine analog, was found to be a potent inhibitor of the growth of nine different human solid tumor cell lines in vitro and of pancreatic carcinoma (DAN) in antithymocyte serum (ATS)-immunosuppressed mice. In culture, IC50 values ranged from 1.1 to 8.5 X 10(-8)M. Ovarian carcinoma (MR) was the only cell line in which the activity of 9-DAA was potentiated (about 10-fold) by pretreatment with the adenosine deaminase inhibitor 2'-deoxycoformycin (dCF). After incubation of cultured pancreatic DAN cells with 9-DAA (10(-5)M) for 2 hr, a peak appeared in the triphosphate region of HPLC nucleotide profiles that was identified tentatively as 9-deazaATP. Under the same incubation conditions, the incorporation of [3H]uridine into RNA and of [3H]thymidine into DNA was inhibited by 34 and 80% respectively. In vivo studies using ATS-immunosuppressed mice showed that 9-DAA at 0.4 mg/kg/day for 3 consecutive days reduced pancreatic carcinoma (DAN) tumor weights to approximately 50% of untreated controls. The nucleoside transport inhibitor p-nitrobenzyl-6-thioinosine (NBMPR) was shown to selectively protect host tissues from 9-DAA toxicity and, thereby, potentiated the antitumor activity of 9-DAA in vivo at optimal dosages.
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D002460:Cell Line; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012263:Ribonucleosides / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D014372:Tubercidin / Q000378:metabolism / Q000494:pharmacology* / Q000031:analogs & derivatives; D014529:Uridine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D012263:Ribonucleosides; C038031:9-deazaadenosine; D014372:Tubercidin; D013936:Thymidine; D014529:Uridine