Reference

Genetic and biochemical studies on the activation and cytotoxic mechanism of bredinin, a potent inhibitor of purine biosynthesis in mammalian cells

Genetic and biochemical studies on the activation and cytotoxic mechanism of bredinin, a potent inhibitor of purine biosynthesis in mammalian cells. Koyama, Hideki; Tsuji, Masae (Cancer Inst., Japanese Found. Cancer Res., Tokyo 170, Japan). Biochem. Pharmacol., 32(23), 3547-53 (English) 1983. CODEN: BCPCA6. ISSN: 0006-2952. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) To study the activation and cytotoxic mechanism of bredinin [50924-49-7], a novel nucleoside antibiotic with potent cytotoxic and immunosuppressive effects, 5 mutants resistant to 10 mM bredinin were isolated from cultured mouse mammary carcinoma FM3A cells mutagenized with N-methyl-N'-nitro-N-nitrosoguanidine. Such bredinin-resistant (Brdr) mutants were 15- to 19-fold less sensitive to the antibiotic than wild-type cells and maintained stably their resistant phenotypes in the absence of bredinin for more than 3 mo. They were cross-resistant to tubercidin [69-33-0], an adenosine analog. Like wild-type cells, Brdr mutants were capable of incorporating radioactivity from ring-labeled adenosine [58-61-7] into the acid-insol. macromol. 68-94-0 and 69-89-6 are also in the experiment. fraction. However, hypoxanthine-guanine phosphoribosyltransferase [9016-12-0]-deficient mutants derived from the Brdr cells did not incorporate the radioactivity at all or at a markedly reduced rate, indicating that blockade of the pathway via adenosine deaminase [9026-93-1] present in the Brdr cells resulted in loss of their ability to utilize adenosine. Enzyme assays using cell-free exts. revealed that all the Brdr mutants had <3% of the adenosine kinase (AK) [9027-72-9] activity found in wild-type cells. These results demonstrate that the bredinin resistance is attributed to a defective AK activity and, therefore, that bredinin is metabolized by AK, which may phosphorylate it to a toxic nucleotide, bredinin 5'-monophosphate (Brd-MP) [62025-48-3], in sensitive cells. Among exogenously added purine bases, guanine [73-40-5] was able to reverse the cytotoxic effect of bredinin on both wild-type cells and F5 cells carrying the vector pSV2-Escherichia coli xanthine-guanine phosphoribosyltransferase [9023-10-3] gene, while xanthine [69-89-6] was able to do so only in F5 cells because the base was metabolized to XMP [523-98-8] by the cells. Apparently, the cytotoxicity of bredinin is due to the formation of Brd-MP in sensitive cells which blocks the conversion of IMP [131-99-7] to XMP by inhibiting IMP dehydrogenase [9028-93-7]. .

Joint study on the teratogenic sensitivity of the pika (Ochotona rufescens rufescens) to selected drugs

Joint study on the teratogenic sensitivity of the pika (Ochotona rufescens rufescens) to selected drugs. Nishimura, Hideo; Shiota, Kohei; Uwabe, Chigako; Nomura, Tatsuji (Cent. Inst. Exptl. Anim., Kawasaki 213, Japan). Exp. Anim., 35(4), 387-408 (English) 1986. CODEN: JIDOAA.In this article, certain chemicals are used. Some of their cas registry numbers are 50-02-2 and 50-44-2 ISSN: 0007-5124. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) A collaborative study was conducted to investigate the teratol. susceptibility of the pika to cyclophosphamide (I) [50-18-0], 6-mercaptopurine [50-44-2], 5-fluorouracil [51-21-8], 6-aminonicotinamide [329-89-5], actinomycin D [50-76-0], ethylurethane [51-79-6], ampicillin [69-53-4], tetracycline [60-54-8], thalidomide [50-35-1], diphenylhydantoin [57-41-0], hypervitaminosis A, aspirin [50-78-2], dexamethasone [50-02-2], betamethasone [378-44-9], and bredinin [50924-49-7]. Some of the chems. were teratogenic in the pika, but this animal was generally more resistant to these compds. than the rabbit and rodents. In the pika, thalidomide did not induce any typical limb defects. Pikas reproduce well and appear to have no substantial disadvantages as an animal species for teratol. studies. Thus, the pika may be useful as a new nonrodent species for teratol. testing. .