Differential oncogene amplification in tumor cells from a patient treated with cisplatin and 5-fluorouracil.
Peritoneal cells were derived from a patient (PK) with adenocarcinoma of the colon during the course of cisplatin/5-fluorouracil (5-FUra) treatment. Resistance to cisplatin and 5-FUra, characterized by a lack of response to chemotherapy and continued growth of the tumor, was concomitantly associated with a 2-4-fold increase in DNA copy number for dTMP synthase and dihydrofolate reductase. There was a corresponding amplification in DNA copy number of the c-myc (2X), H-ras (4X), and c-fos (15X) oncogenes. Cytogenetic studies revealed an iso (13q) chromosome, but failed to show any double minutes or homogeneously staining regions. In addition, drug-resistant tumor cells from PK and another patient (HG) displayed enhanced expression of dTMP synthase, c-fos and DNA polymerase beta when compared to normal colon tissue and the HCT8 human colon carcinoma cell line. These results suggest that elevated oncogene DNA and gene expression may be involved in the development of cisplatin resistance.
Kashani-Sabet
M
M
Biochemical Pharmacology, City of Hope National Medical Center, Duarte, CA 91010.
Lu
Y
Y
Leong
L
L
Haedicke
K
K
Scanlon
K J
KJ
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005784:Gene Amplification / Q000187:drug effects*; D006801:Humans; D008875:Middle Aged; D009857:Oncogenes / Q000187:drug effects*; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary
D002945:Cisplatin; D005472:Fluorouracil