Biochemical pharmacology and experimental chemotherapy studies with guanine-7-oxide, a novel purine antibiotic.
1. Guanine-7-oxide is a novel purine antibiotic produced by a Streptomyces species, ATCC 39364. 2. Guanine-7-oxide is cytotoxic to murine and human leukemia cells in vitro at sub-micromolar concentrations. Murine and human carcinoma cells are much less sensitive. 3. Guanine-7-oxide has significant in vivo antitumor activity, particularly against the intraperitoneal and subcutaneous L1210 leukemia systems. 4. Guanine-7-oxide, at highly cytotoxic concentrations, has little effect on biosynthesis of RNA and DNA. 5. There is preliminary evidence for an early effect of guanine-7-oxide on cellular protein synthesis. 6. Guanine, guanosine and hypoxanthine protect cells from the cytotoxicity of guanine-7-oxide. 7. Activation of guanine-7-oxide requires the presence of the enzyme hypoxanthine-guanine phosphoribosyltransferase in the target cells. 8. Cytotoxic concentrations of guanine-7-oxide do not cause depletion of cellular guanine nucleotides during a two hr incubation period. 9. Guanine-7-oxide is converted within mouse and human cells to a metabolite with chromatographic mobility corresponding to a ribonucleoside 5'-triphosphate.
Jackson
R C
RC
Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan.
Boritzki
T J
TJ
Besserer
J A
JA
Hamelehle
K L
KL
Shillis
J L
JL
Leopold
W R
WR
Fry
D W
DW
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007939:Leukemia L1210 / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D012265:Ribonucleotides / Q000032:analysis
D000903:Antibiotics, Antineoplastic; D009363:Neoplasm Proteins; D012265:Ribonucleotides; C046075:guanine 7-oxide; D006147:Guanine