The cellular pharmacology of oxaliplatin resistance.
Oxaliplatin is a third generation platinum compound that differs from cisplatin and carboplatin in having a broader spectrum of antitumour activity. Molecular studies suggest that oxaliplatin adducts are recognised and processed differently than those produced by the earlier generation Pt-containing drugs. We report here studies on the kinetics of the development of oxaliplatin resistance, and the changes in the cellular pharmacology of oxaliplatin that accompany the emergence of the resistant phenotype in five parental human tumour cell lines and their sub-lines selected for acquired oxaliplatin resistance in vitro. During selection, resistance did not substantially increase until after at least six cycles of oxaliplatin treatment. Oxaliplatin demonstrated schedule-dependency with a 1-h exposure being substantially less cytotoxic than a continuous exposure. Whole cell uptake was linear with concentration, but uptake in the resistant cells averaged only 27+/-10 S.D.% of that in the sensitive cells. Pt accumulation in DNA was markedly reduced in four of the five resistant cell lines, but this did not correlate with either IC(50) or total cellular accumulation. Four of the five resistant sub-lines also demonstrated increased tolerance to adducts in DNA that ranged from 3.1 to 7.6-fold. We conclude that development of acquired resistance to oxaliplatin is accompanied by independent defects in both whole cell uptake and in adduct formation.
Mishima
M
M
Department of Obstetrics and Gynecology, University of Tokyo, Japan.
Samimi
G
G
Kondo
A
A
Lin
X
X
Howell
S B
SB
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000077150:Oxaliplatin; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin