Harrison S D, O'Dwyer P J, Trader M W
Cancer Res. 1986 Jul;46(7):3396-400.
Tiazofurin is a synthetic "C" nucleoside analogue with a promising spectrum of experimental antitumor activity and a relatively novel mechanism of action. Previous work in our laboratories had revealed indications of collateral sensitivity and therapeutic synergism for selected murine tumor models treated with tiazofurin alone or in combination with an antimetabolite or an alkylating agent. Elucidation by others of biochemical indicators of tiazofurin activity provided the rationale for extending our studies to include the tiazofurin combinations reported here. Young, adult, female, BALB/c X DBA/2 F1 mice bearing body burdens of about 4 X 10(7) cells at the start of treatment were used. Cells were implanted either i.p. or s.c. Tiazofurin plus cisplatin or the 5'-palmitate of 1-beta-D-arabinofuranosylcytosine (ara-C) was evaluated against the parent P388/O leukemia line. Tiazofurin plus 6-thioguanine was evaluated against the ara-C-resistant P388. All drug treatments were i.p. injections given daily for 9 days. The experimental design permitted comparison of optimal nontoxic single-agent and two-drug combination regimens on the basis of the estimated log10 change in tumor cell burden at the end of treatment. Concurrent untreated control mice bearing tumor burdens ranging from approximately one to 10(7) cells permitted estimates of cells surviving treatment. Optimal treatment with each of these combinations afforded tumor burden reductions that were greater by 1 to 7 orders of magnitude than the effects of the respective single agents. Optimal single-agent and combination dosages (mg per kg per dose) were as follows: tiazofurin, 500; cisplatin, 2.0; the 5'-palmitate of ara-C, 25; 6-thioguanine, 0.8; tiazofurin, 330 plus cisplatin, 0.58; tiazofurin, 220 plus the 5'-palmitate of ara-C, 20; tiazofurin, 100 plus 6-thioguanine, 0.8. The observed therapeutic synergism of these drugs with tiazofurin in animal models suggests the possibility that treatment with tiazofurin combinations may yield clinical results superior to those obtained with the single agents alone. Therapeutic synergism can be most readily maximized when biochemical markers of drug action are available to provide appropriate clinical-laboratory correlations. Extension of these approaches to the use of tiazofurin, for which biochemical markers and experimental combination chemotherapy leads are now available, would support the rational clinical development of tiazofurin combinations.
替唑呋林是一种合成的“C”核苷类似物，具有很有前景的实验性抗肿瘤活性谱和相对新颖的作用机制。我们实验室之前的工作已经揭示，对于单独使用替唑呋林或与抗代谢物或烷化剂联合使用治疗的特定小鼠肿瘤模型，存在旁敏感性和治疗协同作用的迹象。其他人对替唑呋林活性的生化指标进行的阐释为将我们的研究扩展至包括此处报道的替唑呋林联合用药提供了理论依据。选用治疗开始时体内肿瘤负荷约为4×10⁷个细胞的年轻成年雌性BALB/c×DBA/2 F1小鼠。细胞通过腹腔内或皮下注射植入。评估了替唑呋林加顺铂或1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷）的5'-棕榈酸酯对亲本P388/O白血病细胞系的作用。评估了替唑呋林加6-硫鸟嘌呤对阿糖胞苷耐药的P388细胞的作用。所有药物治疗均为每日腹腔内注射，共9天。该实验设计允许根据治疗结束时肿瘤细胞负荷的估计log₁₀变化，比较最佳无毒单药和两药联合治疗方案。同时设置未治疗的对照小鼠，其肿瘤负荷范围约为1至10⁷个细胞，用于估计治疗后存活的细胞数。这些联合用药的最佳治疗使肿瘤负荷降低的幅度比各自单药治疗的效果大1至7个数量级。最佳单药和联合用药剂量（毫克/千克/剂量）如下：替唑呋林，500；顺铂，2.0；阿糖胞苷的5'-棕榈酸酯，25；6-硫鸟嘌呤，0.8；替唑呋林，330加顺铂，0.58；替唑呋林，220加阿糖胞苷的5'-棕榈酸酯，20；替唑呋林，100加6-硫鸟嘌呤，0.8。在动物模型中观察到的这些药物与替唑呋林的治疗协同作用表明，替唑呋林联合用药治疗可能产生优于单药治疗的临床效果。当有药物作用的生化标志物可用于提供适当的临床-实验室相关性时，治疗协同作用最容易最大化。将这些方法扩展至使用替唑呋林（现在已有其生化标志物和实验性联合化疗线索），将支持替唑呋林联合用药的合理临床开发。
