Dorr R T
Department of Medicine, University of Arizona Medical School, Tucson.
Semin Oncol. 1991 Feb;18(1 Suppl 2):48-58.
Maximal dosing of cytotoxic chemotherapy drugs is often limited by the development of severe nonmyelosuppressive toxicities. Numerous studies have demonstrated that sulfur-containing nucleophiles can antagonize the dose-limiting effects of alkylating agents on the genitourinary tract. Examples include the use of sodium thiosulfate to prevent cisplatin-induced renal tubular necrosis and the use of sulfhydryl-containing compounds like N-acetylcysteine and 2-mercaptoethanesulfonate (mesna) to block oxazophosphorine-induced bladder toxicity. Mesna does not block the antitumor action of oxazophosphorines due to its rapid formation of the inactive dimer dimesna in the bloodstream. The active monomer is selectively reduced from dimesna in renal tubule cells, thereby limiting the inactivation of toxins like acrolein to the genitourinary tract. Recent clinical trials suggest that oral mesna has adequate bioavailability (roughly 50% by urinary thiol measurements) to prevent urotoxicity in high-dose ifosfamide regimens. In addition, mesna is stable in aqueous oral formulations. This may facilitate more convenient oral mesna dosing in protocols using high-dose cyclophosphamide or ifosfamide. Whereas agents like mesna and sodium thiosulfate complex directly with activated (electrophilic) alkylator species, chemoprotectants for the anthracyclines appear to complex with metal cofactors like iron, which are required for the production of cardiotoxicity. Several ethylenediaminetetraacetic-like agents have been evaluated, and a water-soluble piperazinyl derivative, ICRF-187, is currently undergoing clinical evaluation in patients receiving large cumulative doxorubicin doses. An initial clinical trial suggests that ICRF-187 can prevent doxorubicin-induced cardiomyopathy. As with mesna, ICRF-187 does not block the myelosuppressive or the antitumor effects of doxorubicin. Overall, these studies show that site-selective chemoprotection is now feasible for at least two major classes of anticancer agents.
细胞毒性化疗药物的最大剂量常常受到严重非骨髓抑制性毒性反应的限制。大量研究表明，含硫亲核试剂可拮抗烷化剂对泌尿生殖道的剂量限制性影响。例如，使用硫代硫酸钠预防顺铂诱导的肾小管坏死，以及使用含巯基的化合物如N - 乙酰半胱氨酸和2 - 巯基乙烷磺酸盐（美司钠）来阻断氧氮磷啶诱导的膀胱毒性。美司钠不会阻断氧氮磷啶的抗肿瘤作用，因为它在血液中迅速形成无活性的二聚体二巯基乙烷磺酸钠。活性单体在肾小管细胞中从二巯基乙烷磺酸钠选择性还原，从而将丙烯醛等毒素的失活限制在泌尿生殖道。最近的临床试验表明，口服美司钠具有足够的生物利用度（通过尿硫醇测量约为50%），可预防高剂量异环磷酰胺方案中的尿路毒性。此外，美司钠在口服水性制剂中稳定。这可能有助于在使用高剂量环磷酰胺或异环磷酰胺的方案中更方便地口服美司钠给药。虽然美司钠和硫代硫酸钠等试剂直接与活化的（亲电的）烷化剂物种络合，但蒽环类药物的化学保护剂似乎与心脏毒性产生所需的金属辅因子如铁络合。已经评估了几种类似乙二胺四乙酸的试剂，一种水溶性哌嗪基衍生物ICRF - 187目前正在接受大剂量累积阿霉素治疗的患者中进行临床评估。一项初步临床试验表明，ICRF - 187可预防阿霉素诱导的心肌病。与美司钠一样，ICRF - 187不会阻断阿霉素的骨髓抑制或抗肿瘤作用。总体而言，这些研究表明，至少对于两类主要的抗癌药物，部位选择性化学保护现在是可行的。
