O'Brien S, Kantarjian H, Keating M J
University of Texas, M.D. Anderson Cancer Center, Houston, USA.
Ann Oncol. 1996;7 Suppl 6:S27-33. doi: 10.1093/annonc/7.suppl_6.s27.
The observation of lymphopenia in children deficient in adenosine deaminase (ADA) led to exploration of an inhibitor of the enzyme in lymphoid malignancies; thus deoxycoformycin was the first purine nucleotide used in human trials. Fludarabine and 2-chlorodeoxyadenosine (2-CdA), agents resistant to deamination by ADA, have been utilized in the past decade. All of these drugs act as competitors for deoxyadenosine triphosphate at the A sites of the elongating DNA strand, terminating DNA synthesis. However, their remarkable efficacy in indolent lymphoid malignancies is not well explained by this mechanism of action. The induction of apoptosis and resultant cytotoxicity may be important in their activity. As a single agent, fludarabine has been associated with overall remission rates as high as 55% in previously treated patients and 79% in previously untreated patients. With this agent, a dosage regimen of 25-30 mg/m2 daily over 5 days seems to be the most effective to date. Fludarabine has shown more favorable remission rates than the traditional salvage regimens incorporating anthracyclines and alkylating agents. Regimens combining fludarabine with mitoxantrone and with doxorubicin have shown minimal therapeutic advantage in CLL, while combination with cyclophosphamide appears promising. Remission rates with deoxycoformycin have been lower than with fludarabine, but studies have been small in patient numbers. The agent 2-CdA, first successful in hairy-cell leukemia, has shown overall response rates in chronic lymphocytic leukemia similar to those seen with fludarabine. Whether or not cross-resistance occurs among the purine analogs has not been fully determined, but occasional patients with disease refractory to fludarabine have responded to 2-CdA. Cumulative myelosuppression and immunosuppression may be experienced however. In the B-cell neoplastic entity, Waldenström's macroglobulinemia, fludarabine therapy in patients previously treated with alkylating agents and/or steroids produced a 36% response rate. Only two previously untreated patients received fludarabine, and both responded. A similar response rate of 40% was seen when 2-CdA was administered to previously treated patients. This response rate increased to 85% in a study of 26 previously untreated patients, making this one of the most effective drugs yet investigated in this condition.
观察到腺苷脱氨酶（ADA）缺乏的儿童存在淋巴细胞减少症，这促使人们探索该酶在淋巴系统恶性肿瘤中的抑制剂；因此，脱氧助间型霉素是首个用于人体试验的嘌呤核苷酸。氟达拉滨和2-氯脱氧腺苷（2-CdA）是对ADA脱氨基作用有抗性的药物，在过去十年中已被应用。所有这些药物在延伸的DNA链的A位点作为三磷酸脱氧腺苷的竞争剂，终止DNA合成。然而，它们在惰性淋巴系统恶性肿瘤中的显著疗效并不能很好地用这种作用机制来解释。诱导细胞凋亡及由此产生的细胞毒性可能在其活性中起重要作用。作为单一药物，氟达拉滨在既往接受过治疗的患者中的总体缓解率高达55%，在既往未接受过治疗的患者中为79%。使用该药物时，每日25 - 30 mg/m²，持续5天的给药方案似乎是迄今为止最有效的。与包含蒽环类药物和烷化剂的传统挽救方案相比，氟达拉滨显示出更有利的缓解率。氟达拉滨与米托蒽醌以及与阿霉素联合的方案在慢性淋巴细胞白血病（CLL）中显示出最小的治疗优势，而与环磷酰胺联合似乎很有前景。脱氧助间型霉素的缓解率低于氟达拉滨，但研究的患者数量较少。药物2-CdA首先在毛细胞白血病中取得成功，在慢性淋巴细胞白血病中的总体缓解率与氟达拉滨相似。嘌呤类似物之间是否存在交叉耐药性尚未完全确定，但偶尔有对氟达拉滨耐药的患者对2-CdA有反应。然而，可能会出现累积性骨髓抑制和免疫抑制。在B细胞肿瘤实体瓦尔登斯特伦巨球蛋白血症中，氟达拉滨治疗既往接受过烷化剂和/或类固醇治疗的患者产生了36%的缓解率。只有两名既往未接受过治疗的患者接受了氟达拉滨治疗，两人均有反应。当对既往接受过治疗的患者给予2-CdA时，观察到类似的40%的缓解率。在一项对26名既往未接受过治疗的患者的研究中，该缓解率增至85%，使其成为在这种情况下研究过的最有效的药物之一。
