Isolation and characterization of human breast adenocarcinoma cells made resistant to alpha-difluoromethylornithine.
Human breast adenocarcinoma cells MCF-7 were selected for resistance to ornithine decarboxylase (ODC) inhibitor, alpha-difluoromethylornithine (DFMO). Stepwise increments of the concentration of DFMO resulted in selection of MCF-7 cells that were capable of growing in the presence of 1.0 mM DFMO. This capacity was associated with a 10-fold increase in ODC activity and marked enhancement in the synthesis rate of ODC protein as verified by a 2-hr [35S]methionine labeling of cellular proteins followed by immunoprecipitation and SDS-PAGE. The resistant cells had much higher concentration of putrescine, spermidine, and spermine than the control cells. A 25-fold increase in ED50 (effective dose causing 50% inhibition) for the antiproliferative action of DFMO in these resistant cells was observed. The susceptibility of wild-type and resistant cell lines to other inhibitors of the polyamine biosynthetic pathway and adriamycin is also reported.
Das
B
B
School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
Vig
M
M
Khurana
K K
KK
Madhubala
R
R
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D000518:Eflornithine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D009955:Ornithine Decarboxylase; D000518:Eflornithine