Blasiak Janusz, Gloc Ewa, Pertyński Tomasz, Drzewoski Józef
Department of Molecular Genetics University of Lodz, 90-237 Lodz, Poland.
Anticancer Drugs. 2002 Nov;13(10):1055-60. doi: 10.1097/00001813-200211000-00009.
STI571 is a specific ABL family tyrosine kinases inhibitor approved for treatment of leukemias. It can differentially modulate the action of other antileukemic drugs. We have recently shown that deregulation of the mechanisms of DNA damage and repair in BCR/ABL-positive cells may be involved in drug resistance of these cells, and thus determine the response of cancer cells to therapy. In the present work we investigated DNA damage and repair induced by idarubicin in the presence of STI571 and amifostine, a normal cell protector, in the BCR/ABL fusion tyrosine kinase-expressing cell line. Amifostine increased the viability of both kinds of cells in the absence of STI571, but had no effect in the presence of the inhibitor. STI571 did not change the response of both BCR/ABL-expressing cells and their control counterparts to idarubicin in terms of DNA damage and repair. However, the presence of amifostine modulated the response of the cells. In the absence of STI571 amifostine decreased the DNA-damaging effect of idarubicin in normal cells and increased it in BCR/ABL-positive cells. STI571 at 2 M abolished the protective effect of amifostine against idarubicin in normal cells and diminished the magnitude of the amifostine-induce increase in cancer cells. These results suggest that amifostine should be applied with special caution in idarubicin-based chemotherapies of BCR/ABL-positive leukemias involving STI571 inhibitor.
STI571是一种已被批准用于治疗白血病的特异性ABL家族酪氨酸激酶抑制剂。它可以差异性地调节其他抗白血病药物的作用。我们最近发现，BCR/ABL阳性细胞中DNA损伤和修复机制的失调可能与这些细胞的耐药性有关，从而决定癌细胞对治疗的反应。在本研究中，我们在表达BCR/ABL融合酪氨酸激酶的细胞系中，研究了在STI571和正常细胞保护剂氨磷汀存在的情况下，伊达比星诱导的DNA损伤和修复情况。在没有STI571的情况下，氨磷汀增加了两种细胞的活力，但在有抑制剂存在时则没有效果。就DNA损伤和修复而言，STI571并没有改变表达BCR/ABL的细胞及其对照细胞对伊达比星的反应。然而，氨磷汀的存在调节了细胞的反应。在没有STI571的情况下，氨磷汀降低了伊达比星对正常细胞的DNA损伤作用，并增加了其对BCR/ABL阳性细胞的损伤作用。2 μM的STI571消除了氨磷汀对正常细胞中伊达比星的保护作用，并减弱了氨磷汀诱导的癌细胞中DNA损伤增加的程度。这些结果表明，在涉及STI571抑制剂的基于伊达比星的BCR/ABL阳性白血病化疗中，应特别谨慎使用氨磷汀。
