CELLULAR SELECTIVITY OF ANTIMETABOLITES

本建议的目的有两个：（1）了解 组织选择性的生物化学和药理学基础 5-氟尿嘧啶前药，5 ′-脱氧-氟尿嘧啶（5 ′-dFUrd），并评估 代谢调节剂的作用，在选择性调节的 该药物在敏感和相对耐药的 肿瘤的 这包括小鼠中的可移植结肠癌（第26号）， 大鼠结肠癌和裸鼠人Hep-2细胞。 调制器 如甲酰四氢叶酸（CF）和脱氧肌苷（dIno）将被研究，（2） 因为这个实验室的研究揭示了 Ara-C代谢、Ara-CTP保留和响应，体内研究旨在 这些参数在肿瘤细胞中的选择性改变， 对阿糖胞苷的基本活性将得以实现。 包括L1210和P288 肿瘤的 与连续输注相比，使用高剂量阿糖胞苷将 进行研究，以确定反应的决定因素。 具体目标是：（1） 将5 '-dFUrd的体内活化和代谢与抗- 肿瘤活性和组织毒性，以这种药物，（2）以确定是否 CF和dIno可以选择性地改变代谢， 5 '-dFUrd的治疗效果。 游离FdUMP，抑制和恢复 dTMP-合成酶;并将定量药物掺入RNA中。 最终目的是了解生物化学和药理学基础 5 '-dFurd的治疗效果。 (3)去调查 Ara-CTP的细胞内滞留可以选择性地操纵， 肿瘤与正常组织。 将评估高剂量Ara-C方案， 结果将与连续输注 在最佳治疗条件下使用Ara-C。 在P288细胞中， Ara-CTP保留率低，将研究高剂量Ara-C， 确定这种方法在修改本帕拉中的可行性， 测量并评估此类改变的治疗后果，以及 (4)为了利用细胞分离方法来定量药物代谢， 在不同的细胞亚型中进行杂交，试图了解异质性 生化敏感性。 药物代谢研究的结果 相关的分数将与它们的生长速率和 体内药物敏感性。

The objective of this proposal is two-fold: (1) to understand the biochemical and pharmacological basis for the tissue selectivity of 5-fluorouracil prodrug, 5'-deoxy-fluorouridine (5'- dFUrd) and to evaluate the role of metabolic modulators in the selective modulation of the therapeutic efficacy of this agent in sensitive and relatively resistant tumors. This includes transplantable colon carcinoma in mice (No. 26), ward colon tumor in rats, and human Hep-2 cells in nude mice. Modulators such as Leucovorin (CF) and deoxyinosine (dIno) will be studied, (2) since studies from this laboratory revealed a direct relationship between Ara-C metabolism, Ara-CTP retention, and response, studies in vivo aimed at the selective alteration of these parameters in tumor cells with differ- ential sitivity to Ara-C will be carried out. This includes L1210 and P288 tumors. The use of high dose Ara-C as compared to continuous infusion will be studied to identify determinants of response. The specific aims are: (1) to correlate in vivo activation and metabolism of 5'-dFUrd with the anti- tumor activity and tissue toxicity to this drug, (2) to determine whether CF and dIno can selectively modify the metabolism and consequently the therapeutic efficacy of 5'-dFUrd. Free FdUMP, inhibition and recovery of dTMP-synthetase; and incorporation of the drug into RNA will be quantitated. The ultimate aim is to understand the biochemical and pharmacological basis for the therapeutic efficacy of 5'-dFurd. (3) to investigate means by which the intracellular retention of Ara-CTP can be selectively manipulated in tumor vs normal tissues. High dose Ara-C schedule will be evaluated and the results will be compared with these obtained when continuous infusion of Ara-C under optimal therapeutic conditions is employed. In P288 cells were the retention of Ara-CTP is is low, high dose Ara-C will be investigated to determine the feasibility of this approach in the alteration of this para- meter and to evaluate the therapeutic consequences of such alterations, and (4) to utilize cell separation methodologies for quantitation of drug met- abolism in different cell subtypes in an attempt to understand heterogeneity of biochemical sensitivity. The results of drug metabolism studies in relevant fractions will be correlated with their growth rate and with the in vivo drug sensitivity.