5FU, LEUCOVORIN, AZT & PERSANTINE FOR MELANOMA, RENAL, AND COLORECTAL CANCER

5FU和亚叶酸钙(LV)的联合应用已导致显著的 应答率的提高和存活率的适度改善 转移性结直肠癌患者。然而，许多患者是 在发病时耐药，其他人在发病期间产生耐药性 心理治疗。抗性可能是由于胸腺嘧啶核苷通过 细胞内或细胞外破裂的替代抢救途径 DNA的产物。潘生丁抑制核苷在细胞内的转运 膜，从而阻止抢救预先形成的核苷。因此， 细胞外核苷将不能进入细胞，而脂质- 可溶性AZT可以扩散到细胞内，并与任何胸腺嘧啶核苷竞争 由5FU和LV或细胞内的TS抑制逃逸而产生 核苷的回收。这些药物的结合应该会导致 有效的胸腺嘧啶核苷饥饿和细胞死亡。 5FU、LV和潘生丁固定剂量随剂量增加的I期研究 AZT的剂量(50毫克、100毫克和200毫克)已经完成。剂量限制 没有观察到毒性，正在进行第二阶段研究 200 mg剂量的AZT。6例接受50 mg的AZT治疗，5例接受100 mg的治疗，5例接受AZT治疗 在研究的第一阶段期间为200毫克。4级贫血和 分别服用50毫克和100毫克的患者中有一名患者出现4级血小板减少。 剂量水平。200 mg AZT未观察到4级毒性。 肾细胞患者服用100毫克AZT后有一次轻微反应。 癌症。5名服用200毫克AZT的患者中有4名无法评估 以示回应。到目前为止，已有13名患者登记参加第二阶段 研究的一部分：肾脏(6例)、黑色素瘤(4例)和结直肠(3例)。

The combination of 5FU and leucovorin (LV) has resulted in significant increases in response rates and modest improvements in survival for patients with metastatic colorectal cancer. However, many patients are resistant to treatment at presentation and others acquire resistance during therapy. Resistance may be the result of provision of thymidylate via the alternate salvage pathway from intracellular or extracellular breakdown products of DNA. Persantine inhibits nucleoside transport at the cell membrane thereby blocking salvage of preformed nucleosides. Thus, extracellular nucleosides will be unable to enter the cell while lipid- soluble AZT can diffuse into the cell and compete with any thymidine generated by escape of TS inhibition by 5FU and LV or the intracellular salvage of nucleosides. The combination of these agents should lead to effective thymidine starvation and cell death. A phase I study using fixed doses of 5FU, LV and persantine with increasing doses of AZT (50 mg, 100 mg and 200 mg) has been completed. Dose-limiting toxicity was not observed and a phase II study is being conducted at the 200 mg dose of AZT. Six patients received AZT at 50 mg, 5 at 100 mg and 5 at 200 mg during the phase I portion of the study. Grade 4 anemia and grade 4 thrombocytopenia were observed in one patient each at 50 and 100 mg dose levels, respectively. No grade 4 toxicity was observed at 200 mg AZT. There was one minor response at 100 mg of AZT in a patient with renal cell carcinoma. Four of the five patients at 200 mg of AZT are not evaluable for response. Thus far, 13 patients have been enrolled on the phase II portion of the study; renal (6), melanoma (4) and colorectal (3).