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

5 FU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 在出现时对治疗耐药，而其他人在出现时获得耐药。 疗法 耐药性可能是通过免疫抑制剂提供胸苷酸的结果。 细胞内或细胞外降解的替代补救途径 DNA的产物。 潘生丁抑制细胞的核苷转运 膜，从而阻断预先形成的核苷的补救。 因此，在本发明中， 细胞外核苷将无法进入细胞，而脂质- 可溶性AZT可以扩散到细胞中，并与任何胸苷竞争 通过5 FU和LV逃避TS抑制或细胞内 抢救核苷。 这些药物的组合应该会导致 有效的胸苷饥饿和细胞死亡。 一项I期研究，使用固定剂量的5 FU、LV和潘生丁， 已完成AZT剂量（50 mg、100 mg和200 mg）。 剂量限制 没有观察到毒性，正在进行II期研究， 200毫克剂量的AZT 6例患者接受AZT 50 mg，5例接受100 mg，5例接受100 mg， 在研究的I期部分期间以200 mg给药。 4级贫血和 在50和100 mg剂量组各有1例患者观察到4级血小板减少症 剂量水平。 在200 mg AZT时未观察到4级毒性。 有一个轻微的反应，在100毫克的AZT患者肾细胞 carcinoma. 服用200毫克AZT的5名患者中有4名无法评估 来回应。 到目前为止，已有13名患者参加了II期研究。 研究部分;肾脏（6）、黑素瘤（4）和结肠直肠（3）。

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).