Additive apoptotic effect of STI571 with the cytoprotective agent amifostine in K-562 cell line.
OBJECTIVE
To study the apoptotic effect of the 2-phenylaminopyrimidine derivative STI571 in combination with antioxidant agents on K-562 cell line derived from a Philadelphia chromosome-positive chronic myeloid leukemia patient.


METHODS
K-562 (BCR/ABL+), U-937, and HL60 (BCR/ABL-) leukemic cell lines were incubated with STI571 and the antioxidant agents catalase, glutathione, superoxide dismutase, and amifostine (AMI). Apoptotic effect was analyzed by morphological and flow cytometric criteria.


RESULTS
STI571 at concentrations higher than 0.25 mumol L(-1) produced apoptosis (P<0.05) in K-562 cells only after treatment for 72 h. At the mentioned concentrations, STI571 also induced an increase in the loss of mitochondrial transmembrane potential from 24.6 to 40%. Combination of STI571 (0.5 micromol L(-1)) with antioxidant agents showed that the cytoprotective agent AMI (0.75 mg mL(-1)) produced an additive effect in the proapoptotic activity of STI571 in K-562 cells at nuclear (58.8%+/-2.0 vs. 28.9%+/-3.3) and mitochondrial (53.3%+/-3.6 vs. 29.5%+/-1.2) levels.


CONCLUSIONS
Our results show that only AMI in combination with STI571, at submicromolar concentration, has an additive effect in K-562 cell line, and it does not have severe toxic effects on Philadelphia chromosome negative cells.
Vellón
Luciano
L
Depto de Genética, Instituto de Investigaciones Hematológicas Mariano R. Castex, Academia de Medicina, J.A. Pacheco de Melo 3081, 1425 Buenos Aires, Argentina.
González-Cid
Marcela
M
Nebel
Marcelo de Campos
Mde C
Larripa
Irene
I
D004999:Amifostine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D019610:Cytoprotection; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D010879:Piperazines; D011743:Pyrimidines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000975:Antioxidants; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D004999:Amifostine