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

5FU和甲酰四氢叶酸（LV）的组合导致了显著的 反应率提高， 转移性结直肠癌患者。 然而，许多患者 就诊时对治疗耐药，其他人则获得耐药 在治疗期间。 抵抗可能是提供 胸苷酸通过交替补救途径从细胞内或 DNA的胞外分解产物。 潘生丁抑制核苷 在细胞膜上的运输，从而阻止了预先形成的 核苷 因此，细胞外核苷将无法进入 而脂溶性AZT可以扩散到细胞内， 通过5FU和LV逃避TS抑制产生的任何胸苷，或 核苷的细胞内补救。 结合这些 试剂应导致有效的胸苷饥饿和细胞死亡。 使用固定剂量的5FU、LV和潘生丁的I期研究， 已完成AZT剂量的增加（50 mg、100 mg和200 mg）。 未观察到剂量限制性毒性，200 mg AZT剂量为 选择进行II期研究。 黑色素瘤（14例患者）和肾 II期研究的细胞（14例患者）部分已完成 计划中的9名患者中有8名已经累积到结肠 癌症部分。 主要毒性为血液学毒性， III级和22次IV级粒细胞减少症发作。 有五 大于或等于III级血小板减少症的发作和9例 大于或等于III级贫血的发作。 在肾细胞 癌症和转移性黑色素瘤，已经有零个完整的或 部分和三个小的响应。 在结肠癌中， 7例可评价患者部分缓解，1例患者过早缓解 来评估。

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 an AZT dose of 200 mg was chosen for the phase II study. The melanoma (14 patients) and renal cell (14 patients) portions of the phase II study have been completed and eight of a planned nine patients have been accrued to the colon cancer portion. Major toxicity was hematologic, with 13 episodes of grade III and 22 episodes of grade IV granulocytopenia. There were five episodes of greater than or equal to grade III thrombocytopenia and nine episodes of greater than or equal to grade III anemia. In renal cell carcinoma and metastatic melanoma, there have been zero complete or partial and three minor responses. In colon cancer, there has been one partial response in seven evaluable patients, with one patient too early to evaluate.