Activity and Mechanism of Action of 6-Methylthiopurine Ribonucleoside in Cancer Cells Resistant to 6-Mercaptopurine

Bennett, L. Lee; Brockman, R. W.; Schnebli, P.; Chumley, Sue; Dixon, Glen J.; Schabel, Frank M.; Dulmadge, Elizabeth A.; Skipper, Howard E.; Montgomery, John A.; Thomas, H. Jeanette

doi:10.1038/2051276a0

Cited by 81 publications

(15 citation statements)

References 16 publications

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“…MMPR is effective as a pseudofeedback inhibitor of purine biosynthesis. 2 Whether or not this is the major mechanism of tumor inhibition by MMPR remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…(> The solvent systems for ascending development were the following (all proportions were v Iv) : (A) n-butanol-propionic acid-water (469: 220:311), 2 (B) n-butanol-acetic acidwater (25: 15: 1O),z (C) ammonium sulfate (5 per cent in water )-isopropanol (5 per cent in water) (1: 1), 9 (D) methanol-concentrated hydrochloric acid-water (7: 2: 1),9 (E) disodium hydrogen phosphate (5 per cent in water )-isopropanol (5 per cent in water) (3:2),9 (F) dicyclohexylamine-butanone-water (2:10:5),2 and (G) t-butanol-butanone-water-diethylamine (4: 4:2:4). 2 After development, the plate was carefully dried in a current of warm air, and scanned with a Packard radiochromatogram scanner, model 7201. Fluorescent spots were located under ultraviolet lights of 254 or 366 mft.…”

Section: Clinical Pharmacologymentioning

confidence: 99%

See 1 more Smart Citation

Clinical pharmacologic observations on 6‐mercaptopurine and 6‐methylthiopurine ribonucleoside

Loo

Luce

Sullivan

et al. 1968

Clin Pharma and Therapeutics

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“…MMPR is effective as a pseudofeedback inhibitor of purine biosynthesis. 2 Whether or not this is the major mechanism of tumor inhibition by MMPR remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Section: Clinical Pharmacologymentioning

confidence: 99%

Clinical pharmacologic observations on 6‐mercaptopurine and 6‐methylthiopurine ribonucleoside

Loo

Luce

Sullivan

et al. 1968

Clin Pharma and Therapeutics

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“…It is not readily converted to di-and triphosphate, but as the monophosphate, it is a potent feedback inhibitor of the initial step in purine synthesis de novo. It is indeed effective against some experimental tumors resistant to 6-MP (Bennett et al, 1965). A cell line resistant to MMPR was found to lack adenosine kinase (Caldwell et al, 1976).…”

Section: Derivativesmentioning

confidence: 96%

Purine Antagonists

LePage¹

1977

Chemotherapy

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“…Azaserine is a glutamine analog that is a competitive inhibitor of glutamine-requiring steps of de novo synthesis (Levenberg et al, 1957;Becker and Kim, 1987). MMPR is an adenosine analog that is phosphorylated by adenosine kinase and in the phosphorylated state negatively feeds back on the enzyme, phosphoribosyl pyrophosphate amidotransferase, which catalyzes the first committed reaction of purine de novo synthesis (Bennett et al, 1965;Tay et al, 1969). Preliminary experiments determined that the accumulation of purines from de novo synthesis was linear through 3 h of culture; subsequent experiments therefore used 3 h as the incubation period.…”

Section: A Comparison Of the Effects Of Purine Metabolic Inhibitors Omentioning

confidence: 99%

Purine control of mouse oocyte maturation: Evidence that nonmetabolized hypoxanthine maintains meiotic arrest

Downs

1993

Molecular Reproduction Devel

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Hypoxanthine is present in preparations of follicular fluid and has been shown to suppress the spontaneous meiotic maturation of mammalian oocytes in vitro. The present experiments examined the possible role of hypoxanthine metabolism in mediating this meiotic arrest. Four putative inhibitors of the enzyme, hypoxanthine phosphoribosyltransferase (HPRT), which metabolizes hypoxanthine to inosine monophosphate, were tested on lysates of oocyte-cumulus cell complexes. At a concentration of 1 mM, 6-mercapto-9-(tetrahydro-2-furyl)-purine (MPTF) and 6-mercaptopurine (6-MP) suppressed enzymatic activity by 86% and 98%, respectively, while 6-azauridine and 2,6-bis-(hydroxyamino)-9-beta-D-ribofuranosyl-purine had no effect. MPTF and 6-MP increased the inhibitory effect of hypoxanthine on germinal vesicle breakdown, but the other agents did not. The 2 active agents had similar effects on salvage activity and hypoxanthine-maintained meiotic arrest in denuded oocytes. Also, oocytes from XO mice were more sensitive to the meiosis-arresting action of hypoxanthine than oocytes from XX littermates, which have twice the HPRT activity. The actions of the HPRT inhibitors were not due to their conversion to nucleotides via HPRT and negative feedback on purine de novo synthesis, because azaserine and 6-methylmercaptopurine riboside, which are more potent inhibitors of de novo synthesis, had a stimulatory, rather than inhibitory, effect on hypoxanthine-arrested oocytes. Furthermore, several lines of evidence indicate that metabolism of hypoxanthine to xanthine and uric acid by xanthine oxidase does not mediate the inhibitory action of this purine base on meiotic maturation. The data therefore suggest that nonmetabolized hypoxanthine is responsible for the meiotic arrest observed, most likely through suppression of cAMP degradation.

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Activity and Mechanism of Action of 6-Methylthiopurine Ribonucleoside in Cancer Cells Resistant to 6-Mercaptopurine

Cited by 81 publications

References 16 publications

Clinical pharmacologic observations on 6‐mercaptopurine and 6‐methylthiopurine ribonucleoside

Clinical pharmacologic observations on 6‐mercaptopurine and 6‐methylthiopurine ribonucleoside

Purine Antagonists

Purine control of mouse oocyte maturation: Evidence that nonmetabolized hypoxanthine maintains meiotic arrest

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