Correlation between decreased apoptosis and multidrug resistance in murine leukemic T cell lines

LOPES EC; GARCÍA MG; VELLÓN L; ALVAREZ E; HAJOS S

San Francisco, CA- USA

Congreso; 37th Annual Meeting of American Society of Clinical Oncology (ASCO); 2001

ASCO

Cancer cells may frequently develop cross-resistance to structurally dissimilar chemotherapeutic agents. However, the molecular mechanisms for sensitivity and resistance of tumor cells towards chemotherapy are still partially understood. Antineoplastic drugs have been shown to induce apoptosis in chemosensitive leukemias and solid tumors. In this work, cross-resistance among vincristine (VCR), doxorubicin (DOX) and other antineoplastic agents commonly used in the treatment of leukemia such as etoposide (VP-16), methotrexate (MTX), cyclophosphamide (CTX), dexamethasone (DEX), cytarabine (Ara-C) and l-asparaginase on vincritine resistant (LBR-V160), doxorubicin resistant (LBR-D160) and sensitive (LBR-) murine leukemic T cell lines was determined. The effect of these agents was assayed by tritiated thymidine incorporation. Resistance factor for the above drugs for LBR-V160 cell lines were as follows: VCR 111.6 (89.6-133.0), DOX 24.7 (19.2-30.2), VP-16 7.8 (4.8-10.7), DEX 12.5 (10.2-14.9), Ara-C 1.5 (0.8-1.3) and MTX 3.9 (2.1-5.7), while for LBR-D160 cell lines values were VCR 76.3 (61.6-91.0), DOX 67.0 (52-83.1), VP-16 13.7 (0.2-27-6), DEX 0.6 (0.3-0.9), Ara-C 1.0 (0.8-1.3) and MTX 3.3 (1.4-5.2). These results demonstrated that VCR and DOX showed a high degree of cross-resistance, while resistance levels between VCR or DOX with remaining drugs were moderate for DEX (only for VCR) and for VP-16, low for MTX and lacking for Ara-C. Apoptosis induced by the above drugs was analyzed  by acridine orange and ethidium bromide staining, DNA hypoploidy (Flow cytometry) and fragmentation of nuclear DNA. When 0.5 mg/ml of drugs were used, apoptotic indexes obtained comparing sensitive and resistant cell lines were: for VP-16 on LBR- (63.35%), LBR-V160 (10.98%) and LBR-D160 (6.33%) (P<0.01), for DEX on LBR- (5.2%), LBR-V160 (19.97%) (P<0.01) and LBR-D160 (35.02%) (P<0.05). Neither Ara-C nor MTX showed significant differences in apoptotic index between sensitive and resistant cell lines. Our results demonstrated that, except for DEX, none of the drugs presenting cross-resistance were able to induce death on LBR-V160 or LBR-D160 cell lines.