Oncolytic activity and mechanism of action of a novel L-cysteine derivative, L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride.

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Jayaram HN, Lui MS, Plowman J, Pillwein K, Reardon MA, Elliott WL, Weber G

Oncolytic activity and mechanism of action of a novel L-cysteine derivative, L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride.

Cancer Chemother Pharmacol. 1990;26(2):88-92.

PubMed ID

2347042 [ View in PubMed

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Abstract

A study on the oncolytic activity of the L-cysteine derivative L-cysteine, ethyl ester, S-(N-methylcarbamate) monohydrochloride (NSC 303861), revealed that the drug caused complete regression of the MX-1 human mammary tumor xenograft. The compound also exhibited moderate antitumor activity against murine leukemia P388 (T/C value of 169% at a daily dose of 400 mg/kg) and against M5076 sarcoma (T/C value of 135% at a daily dose of 600 mg/kg). The drug was inactive against B16 melanoma, Lewis lung, colon 38 and CD8F1 mammary carcinomas. The compound exhibited significant cytotoxicity against hepatoma 3924A cells in culture (LC50 = 6 microM). Studies on the mechanism of action revealed that the cytotoxicity of the drug could be partially abrogated by protecting hepatoma 3924A cells in culture with L-glutamine. At 6 h after injection of the compound (400 mg/kg) into rats bearing hepatoma 3924A, the pools of L-glutamine and L-glutamate in the tumor decreased to 33% and 71%, respectively, of control levels; the drug selectively inhibited the activities of L-glutamine-requiring enzymes of purine nucleotide biosynthesis, amidophosphoribosyltransferase, FGAM synthase, and GMP synthase, to 21%, 1%, and 69%, respectively, without significantly altering the activities of pyrimidine biosynthetic enzymes, carbamoylphosphate synthase II and CTP synthase. Measurement of the nucleotide concentrations further corroborated the actions of the drug on the purine nucleotide biosynthetic enzyme activities. Drug injection (400 mg/kg) in the hepatoma 3924A-bearing rats reduced the concentrations of IMP in the tumor to 52%, those of total adenylates to 52%, those of total guanylates to 57%, and those of NAD to 73%, without significantly perturbing the pyrimidine nucleotide pools. Studies on the mechanism of action of the L-cysteine derivative suggested that the compound behaved as an L-glutamine antagonist, selectively acting on the enzymes of purine nucleotide biosynthesis.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Glutamic acid	Phosphoribosylformylglycinamidine synthase	Protein	Humans	Unknown	Not Available	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
L-Glutamine	Phosphoribosylformylglycinamidine synthase	Protein	Humans	Unknown	Substrate	Details