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.

中文翻译：

---

新型L-半胱氨酸衍生物，L-半胱氨酸，乙酯，S-（N-甲基氨基甲酸酯）一盐酸盐的溶瘤活性和作用机理。

对L-半胱氨酸衍生物L-半胱氨酸，乙酯，S-（N-甲基氨基甲酸酯）一盐酸盐（NSC 303861）的溶瘤活性的研究表明，该药物导致MX-1人乳腺肿瘤异种移植物完全消退。该化合物还显示出对鼠白血病P388（在400 mg / kg的日剂量下T / C值为169％）和对M5076肉瘤（在600 mg / kg的日剂量下T / C值为135％）的中等抗肿瘤活性。 ）。该药物对B16黑色素瘤，路易斯肺，结肠38和CD8F1乳腺癌无活性。该化合物对培养中的肝癌3924A细胞表现出明显的细胞毒性（LC50 = 6 microM）。作用机理的研究表明，通过用L-谷氨酰胺保护培养的肝癌3924A细胞，可以部分消除药物的细胞毒性。在向患有肝癌3924A的大鼠中注射化合物（400 mg / kg）后的6小时内，肿瘤中L-谷氨酰胺和L-谷氨酸的库分别降至对照水平的33％和71％。该药物将嘌呤核苷酸生物合成所需的L-谷氨酰胺酶，酰胺基磷酸核糖基转移酶，FGAM合酶和GMP合酶的活性分别抑制至21％，1％和69％，而没有显着改变嘧啶生物合成酶的活性，氨基甲酰磷酸合酶II和CTP合酶。核苷酸浓度的测量进一步证实了药物对嘌呤核苷酸生物合成酶活性的作用。荷瘤3924A大鼠的药物注射（400 mg / kg）使肿瘤中IMP的浓度降至52％，总腺苷酸的浓度降至52％，总鸟苷酸含量达到57％，NAD含量达到73％，而不会显着干扰嘧啶核苷酸库。对L-半胱氨酸衍生物的作用机理的研究表明，该化合物起L-谷氨酰胺拮抗剂的作用，选择性地作用于嘌呤核苷酸生物合成的酶。