Increased sensitivity to 1-beta-D-arabinofuranosylcytosine in P388 murine leukemic cells resistant to etoposide.
A variant P388 murine leukemic cell resistant to 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidine)-beta-D-gl ucopyranoside (etoposide) (VP-16-213) was cloned. The variant P388/VP-16 cell line was 159-fold resistant to VP-16. We found that this variant P388/VP-16 cell line showed collateral drug sensitivity to 1-beta-D-arabinofuranosylcytosine(Ara-C), determined by comparing the 50% inhibitory concentrations in 48-h growth inhibition assay. To clarify the mechanism of this increased sensitivity to Ara-C, we quantified the deoxyribonucleoside triphosphate pools and 1-beta-D-arabinofuranosylcytosine triphosphate(Ara-CTP) using high-performance liquid chromatography in the parent and drug-resistant sublines of P388 cells. The analysis of deoxyribonucleoside triphosphate pools revealed that the pyrimidine triphosphate pools were significantly decreased in the P388/VP-16 cell line and the Ara-CTP concentration of two variant cell lines were not significantly different. The Ara-CTP/dCTP ratio was significantly increased in P388/VP-16 cells. These data suggest that the inhibition of the dCTP de-novo pathway and the preservation of the dCTP salvage pathway in P388/VP-16 cells might correlate with the increased sensitivity to Ara-C.
Higashigawa
M
M
Department of Pediatrics, Mie University School of Medicine, Japan.
Ido
M
M
Ohkubo
T
T
Kawasaki
H
H
Kamiya
H
H
Sakurai
M
M
Taniguchi
K
K
Hamazaki
M
M
D000818:Animals; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D003561:Cytarabine / Q000494:pharmacology*; D003854:Deoxyribonucleotides / Q000378:metabolism; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology*; D007941:Leukemia P388 / Q000378:metabolism / Q000473:pathology*; D007942:Leukemia, Experimental / Q000473:pathology*; D051379:Mice
D003854:Deoxyribonucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D005047:Etoposide