Kano Y, Akutsu M, Tsunoda S, Mano H, Sato Y, Honma Y, Furukawa Y
Division of Hematology and Medical Oncology, Tochigi Cancer Center, Tochigi, Japan.
Blood. 2001 Apr 1;97(7):1999-2007. doi: 10.1182/blood.v97.7.1999.
The BCR/ABL tyrosine kinase has been implicated in the pathogenesis of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). STI571 is a novel anticancer agent that selectively inhibits the BCR/ABL tyrosine kinase. The cytotoxic effects of STI571 were studied in combination with antileukemic agents against Ph(+) leukemia cell lines, KU812, K-562, TCC-S, and TCC-Y. The cells were exposed to STI571 and to other agents simultaneously for 5 or 7 days. Cell growth inhibition was determined by MTT assay. The cytotoxic effects in combinations at the inhibitory concentration of 80% level were evaluated by the isobologram. STI571 produced synergistic effects with recombinant and natural alpha-interferons in 2 of 3 and 3 of 3 cell lines, respectively. STI571 produced additive effects with hydroxyurea, cytarabine, homoharringtonine, doxorubicin, and etoposide in all 4 cell lines. STI571 with 4-hydroperoxy-cyclophosphamide, methotrexate, or vincristine produced additive, antagonistic, and synergistic effects in 3 of 4 cell lines, respectively. These findings suggest that the simultaneous administration of STI571 with other agents except methotrexate would be advantageous for cytotoxic effects against Ph(+) leukemias. Among them, the simultaneous administration of STI571 and alpha-interferons or vincristine would be highly effective against Ph(+) leukemias and these combinations would be worthy of clinical trials. In contrast, the simultaneous administration of STI571 with methotrexate would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving STI571. (Blood. 2001;97:1999-2007)
BCR/ABL酪氨酸激酶与慢性粒细胞白血病（CML）及费城染色体阳性（Ph(+)）急性淋巴细胞白血病（ALL）的发病机制有关。STI571是一种新型抗癌药物，可选择性抑制BCR/ABL酪氨酸激酶。研究了STI571与抗白血病药物联合对Ph(+)白血病细胞系KU812、K-562、TCC-S和TCC-Y的细胞毒性作用。细胞同时暴露于STI571和其他药物中5天或7天。通过MTT法测定细胞生长抑制情况。采用等效线图评估在80%抑制浓度水平下联合用药的细胞毒性作用。STI571分别与重组α干扰素和天然α干扰素在3个细胞系中的2个以及3个细胞系中的3个产生协同作用。STI571与羟基脲、阿糖胞苷、高三尖杉酯碱、阿霉素和依托泊苷在所有4个细胞系中均产生相加作用。STI571与4-氢过氧环磷酰胺、甲氨蝶呤或长春新碱分别在4个细胞系中的3个产生相加、拮抗和协同作用。这些发现表明，除甲氨蝶呤外，STI571与其他药物同时给药对Ph(+)白血病的细胞毒性作用可能具有优势。其中，STI571与α干扰素或长春新碱同时给药对Ph(+)白血病可能非常有效，这些联合用药值得进行临床试验。相比之下，STI571与甲氨蝶呤同时给药几乎没有治疗效果。尽管体外研究与临床试验之间存在差距，但目前的研究结果为制定涉及STI571的临床方案提供了有用信息。（《血液》.2001年；97:1999 - 2007）
