Drug control of Ara-C-resistant tumor cells.
Drug control of Ara-C-resistant tumor cells.
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Ara-C 耐药肿瘤细胞的药物控制。
DOI：
10.1002/mpo.2950100713
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发表时间：
1982
期刊：
影响因子：
--
通讯作者：
GriswoldJr,DP
中科院分区：
文献类型：
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作者：
SchabelJr,FM;Skipper,HE;Trader,MW;Brockman,RW;LasterJr,WR;Corbett,TH;GriswoldJr,DP
1-β-D-阿拉伯呋喃糖胞嘧啶 (Ara-C) 是许多临床上有用但通常不是治疗性药物组合的重要组成部分，用于治疗成人急性髓系白血病。它对高生长分数鼠白血病（包括 L1210 和 P388）具有显着的活性。使用 Ara-C 对 L1210 或 P388 身体负担较大的小鼠以及对小鼠可移植性结肠癌（结肠 36）显着敏感的小鼠进行广泛试验，一致表明，通过 Ara-C 治疗未能治愈这些肿瘤是由于 Ara-C 耐药肿瘤细胞过度生长。临床上有用的抗癌剂，包括烷化剂、与 DNA 结合或嵌入的药物、其他类别的抗代谢物和有丝分裂抑制剂。实验数据表明，通过同时、交替或顺序递送 Ara-C 加其他非交叉耐药性药物，可以在治疗携带大量 L1210 或 P388 细胞的小鼠时获得显着的治疗改善（包括许多治愈）。许多其他抗癌药物也是从头抑制剂嘧啶合成[5-氟尿嘧啶 (5-FU)、3-脱氮尿苷、二氢-5-氮杂胞嘧啶、N-(膦酰基 1)-L-天冬氨酸 (PALA) 和吡唑呋林]已被证明对 Ara-C 耐药性 L1210 和/或 P388 细胞（附带敏感性）的体内细胞毒性比对 Ara-C 敏感的 L1210 和/或P388细胞。 palmO-Ara-C（Ara-C 的 5'-棕榈酸酯）与 PALA 联合使用，对晚期 P388 具有显着的治疗协同作用。在药物治疗开始时，肿瘤已经发展到足够晚期，仅用 palmO-Ara-C 治疗失败，因为治疗开始时存在 Ara-C 耐药性肿瘤细胞过度生长。添加 PALA 本身对 Ara-C 敏感的 P388 无效，但对 Ara-C 耐药的 P388 具有明显的细胞毒性，导致大多数（如果不是全部）Ara-C 耐药细胞被杀死。用 palm0-Ara-C 加 3-脱氮尿苷（一种对 Ara-C 耐药的 L1210 细胞表现出附带敏感性的药物）针对晚期 L1210 的类似试验未能显示出改善的治疗反应，可能是由于药物组合对重要正常细胞的毒性增加。 Ara-C 加 5-W、二氢-5-氮杂胞苷或吡唑呋林尚未进行研究。palO-Ara-C 和二羟基蒽二酮 (DiOHA) 之间的治疗协同作用（包括许多治疗）已在小鼠中针对 > 108P388 细胞的身体负担显示出来。这种程度的肿瘤细胞的身体负担导致单独使用 palmO-Ara-C 或 DiOHA 时无法治愈。Ara-C 耐药性 L1210 在体内与 2-氟-9-P-D-阿拉伯呋喃糖腺嘌呤 (2-F-Ara-A) 具有交叉耐药性，这一事实导致研究表明 2-F-Ara-A 通过脱氧胞苷激酶磷酸化为其 5'-单磷酸盐，因此解释了 Ara-C 耐药性 L1210 对 2-F-Ara-A 治疗的交叉耐药性。在细胞对 Ara-C 耐药性的生化基础上获得的基本信息（以及 Ara-C 耐药性肿瘤细胞对其他药物的交叉耐药性和缺乏交叉耐药性）以及 Ara-C 耐药性细胞对某些其他药物附带敏感的观察结果似乎为未来化疗方案的设计提供了背景。
1‐β‐D‐Arabinofuranosylcytosine (Ara‐C) is an important component of a number of clinically useful but usually not curative drug combinations used to treat acute myeloid leukemia of adults. It has marked activity against high growth fraction murine leukemias, including L1210 and P388. Extensive trials with Ara‐C treatment of mice with large body burdens of L1210 or P388 and a markedly sensitive transplantable colon carcinoma of mice (colon 36) have consistently shown that failure to cure these tumors by treatment with Ara‐C is due to the overgrowth of Ara‐C‐resistant tumor cells.L1210 and P388 cells that are resistant to Ara‐C retain essentially unchanged sensitivity to representatives of all of the other major chemical and functional classes of clinically useful anticancer agents including alkylating agents, drugs that bind to or intercalate with DNA, other classes of antimetabolites, and mitotic inhibitors.Experimental data show that marked therapeutic improvement (including many cures) can be obtained on treating mice bearing large body burdens of L1210 or P388 cells by simultaneous, alternating, or sequential delivery of Ara‐C plus other non‐cross‐resistant drugs.A number of other anticancer drugs, which are also inhibitors of de novo pyrimidine synthesis [5‐fluorouracil (5‐FU), 3‐deazauridine, dihydro‐5‐azacyti‐dine, N‐(phosphonacety1)‐L‐aspartate (PALA), and pyrazofurin] have been shown to be orders of magnitude more cytotoxic in vivo against Ara‐C‐resistant L1210 and/or P388 cells (collateral sensitivity) than against Ara‐C‐sensitive L1210 and/or P388 cells. Marked therapeutic synergism has been shown against advanced P388 by the combination of palmO‐Ara‐C (the 5′‐palmitate of Ara‐C) plus PALA. The tumor was sufficiently advanced at start of drug treatment that treatment with palmO‐Ara‐C alone failed, due to overgrowth of Ara‐C‐resistant tumor cells present at start of therapy. The addition of PALA, in itself not effective against Ara‐C‐sensitive P388 but markedly cytotoxic for Ara‐C‐resistant P388, resulted in kill of most, if not all, of the Ara‐C‐resistant cells.Similar trials against advanced L1210 with palm0‐Ara‐C plus 3‐deazauridine (a drug to which Ara‐C‐resistant L1210 cells show collateral sensitivity) have failed to show improved therapeutic response, presumably due to increased toxicity of the drug combination for vital normal cells. Ara‐C plus 5‐W, dihydro‐5‐azacytidine, or pyrazofurin have not yet been studied.Therapeutic synergism between palmO‐Ara‐C and dihydroxyanthracenedione (DiOHA), including many cures, was shown against body burdens of > l08P388 cells in mice. Body burdens of tumor cells of this magnitude assured failure to cure with palmO‐Ara‐C or DiOHA when used alone.The fact that Ara‐C resistant L1210 was cross‐resistant to 2‐fluoro‐9‐P‐D‐ara‐ binofuranosyladenine (2‐F‐Ara‐A) in vivo led to studies which indicated that 2‐F‐Ara‐A is phosphorylated to its 5′‐monophosphate by deoxycytidine kinase, thus explaining the cross‐resistance of Ara‐C‐resistant L1210 to treatment with 2‐F‐Ara‐A.Basic information gained on the biochemical basis of cellular resistance to Ara‐C (and the cross‐resistance and lack of cross‐resistance of Ara‐C‐resistant neoplastic cells to other drugs) and observations that Ara‐C‐resistant cells are collaterally sensitive to certain other agents seems to provide the background for design of future chemotherapeutic regimens.