Francis G E, Mufti G J, Knowles S M, Berney J J, Guimaraes J E, Secker-Walker L M, Hamblin T J
Department of Haematology, Royal Free Hospital, London, U.K.
Leuk Res. 1987;11(11):971-7. doi: 10.1016/0145-2126(87)90115-9.
DNA synthesis inhibitors and vincristine greatly enhance the response of leukaemic and dysplastic cells to differentiation inducing agents such as retinoic acid (RET). Differentiation induction therapy is an attractive therapeutic approach in myelodysplasia (MDS) and in acute myeloid leukaemia (AML) in the elderly, since it should be possible to increase the production of mature cells, at the expense of precursor cells, without incurring the complications of intensive cytotoxic therapy. Single agent differentiation therapy has, however, not been highly successful. We have therefore investigated the use of synergistic combinations of agents. We treated nine patients (6 with MDS, 3 with AML) with 13-cis-retinoic acid (up to 100 mg/m2/day) in combination with either 6-thioguanine (20-40 mg/day in 14-57 day courses) or with vincristine (1-2 mg as a single injection during a four-day course of RET). Seven patients responded with an increase in the mature cells of at least one haemopoietic lineage. A concomitant decrease in marrow blasts was observed in 3/4 responding patients. The retention of dysplastic and karyotypic abnormalities and lack of a hypoplastic phase all suggested that differentiation induction was occurring in vivo. Prior failure to respond to therapy with single agents (RET in two and cytosine arabinoside in five patients) suggests that the synergy observed in vitro operates in vivo. In-vitro studies on marrow cells from seven patients demonstrated synergistic differentiation induction in 6/7 samples. The seventh patient was one of the two who did not respond clinically. The second of these clinically unresponsive patients had cells which were relatively refractory to RET in vitro, suggesting that in-vivo and in-vitro responses may be related.
DNA合成抑制剂和长春新碱可极大增强白血病细胞和发育异常细胞对分化诱导剂（如维甲酸（RET））的反应。分化诱导疗法在骨髓增生异常综合征（MDS）和老年急性髓系白血病（AML）中是一种有吸引力的治疗方法，因为应该有可能以牺牲前体细胞为代价来增加成熟细胞的产生，而不会引发强化细胞毒性疗法的并发症。然而，单药分化疗法并未取得很大成功。因此，我们研究了联合使用具有协同作用的药物。我们用13 - 顺式维甲酸（高达100 mg/m²/天）联合6 - 硫鸟嘌呤（在14 - 57天疗程中每天20 - 40 mg）或长春新碱（在为期四天的RET疗程中单次注射1 - 2 mg）治疗了9例患者（6例MDS，3例AML）。7例患者出现至少一种造血谱系的成熟细胞增加。在4例有反应的患者中，有3例观察到骨髓原始细胞同时减少。发育异常和核型异常的持续存在以及缺乏造血功能低下期均提示体内正在发生分化诱导。先前对单药治疗（2例患者用RET，5例患者用阿糖胞苷）无反应表明，体外观察到的协同作用在体内也起作用。对7例患者骨髓细胞的体外研究表明，7个样本中有6个出现协同分化诱导。第7例患者是2例临床无反应者之一。这2例临床无反应患者中的第二例其细胞在体外对RET相对耐药，提示体内和体外反应可能相关。
