Roberts J C, Francetic D J, Zera R T
Department of Medicinal Chemistry, University of Utah, Salt Lake City 84112.
Cancer Chemother Pharmacol. 1991;28(3):166-70. doi: 10.1007/BF00685504.
2(R,S)-D-ribo-(1',2',3',4'-Tetrahydroxybutyl)-thiazolidine-4(R)-ca rboxylic acid (RibCys) is a prodrug of L-cysteine that releases the sulfhydryl amino acid after nonenzymatic ring opening and hydrolysis. The L-cysteine then elevates glutathione (GSH) levels by stimulating its biosynthesis. RibCys was investigated for its ability to protect CDF1 mice from the potent urotoxicity of cyclophosphamide (CTX) without compromising the therapeutic utility of the drug. RibCys induced a significant reduction in weight loss of the animals and in bladder inflammation at 48 h after CTX administration; however, bladder tissue remained inflamed as compared with that in controls. Bladder histology also showed some pathological changes in the presence of RibCys. In contrast, all parameters of toxicity (body weight loss, bladder inflammation, and pathological abnormalities) had been virtually reversed by day 21 after administration. In tests against L1210 leukemia, RibCys did not interfere with CTX anticancer activity. From these preliminary studies, RibCys appears to be a likely candidate for protecting against long-term CTX toxicity, perhaps reversing the original damage caused by a very high dose, without compromising the therapeutic utility of the alkylating agent.
2（R，S）-D-核糖-（1'，2'，3'，4'-四羟基丁基）-噻唑烷-4（R）-羧酸（RibCys）是L-半胱氨酸的前药，在非酶促开环和水解后释放巯基氨基酸。然后，L-半胱氨酸通过刺激其生物合成来提高谷胱甘肽（GSH）水平。研究了RibCys保护CDF1小鼠免受环磷酰胺（CTX）强大的尿毒性影响的能力，同时又不损害该药物的治疗效用。在CTX给药后48小时，RibCys使动物体重减轻和膀胱炎症显著减轻；然而，与对照组相比，膀胱组织仍有炎症。膀胱组织学检查也显示在有RibCys存在的情况下有一些病理变化。相比之下，给药后第21天，所有毒性参数（体重减轻、膀胱炎症和病理异常）几乎都已恢复正常。在针对L1210白血病的试验中，RibCys不干扰CTX的抗癌活性。从这些初步研究来看，RibCys似乎是预防CTX长期毒性的一个可能候选药物，或许能逆转高剂量CTX造成的原有损伤，同时又不损害烷化剂的治疗效用。
