The effect of retinoic acid on chemosensitivity of PA-1 human teratocarcinoma cells and its modulation by an activated N-ras oncogene.
Combination of chemotherapeutic drugs with agents that induce cell differentiation is a possible means of improving cancer chemotherapy. To explore this approach we used 4 cell lines established from the human teratocarcinoma-derived cell line PA-1; 2 retinoic acid (RA)-sensitive lines compared to 2 RA-resistant lines transformed by an activated N-ras oncogene. Equal numbers of colony-forming cells were exposed for 72 hr to 10(-6)M RA and subsequently to a range of concentrations of cisplatinum, etoposide or bleomycin. Enhanced cytotoxicity of cisplatin and etoposide (3- to 5-fold) was observed in the N-ras-transformed cell lines compared to the non-transformed lines. Treatment with RA caused an increase in the cytotoxicity of all 3 drugs to the 2 RA-sensitive cell lines. In contrast, a reduction of cytotoxicity was observed in the 2 N-ras-transformed lines. Our results indicate that sensitivity to cytotoxic agents can be increased by RA in RA-sensitive cells, but the opposite effect is seen in N-ras transformed, RA-resistant cells. Therefore, a general rationale for combination therapy with RA and cytotoxic drugs cannot be inferred.
Le-Ruppert
K
K
Institute of Pathology, University of Regensburg, Germany.
Masters
J R
JR
Knuechel
R
R
Seegers
S
S
Tainsky
M A
MA
Hofstaedter
F
F
Buettner
R
R
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001761:Bleomycin / Q000494:pharmacology; D002461:Cell Line, Transformed / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005353:Fibronectins / Q000032:analysis; D011905:Genes, ras; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D013724:Teratoma / Q000188:drug therapy / Q000235:genetics*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*
D005353:Fibronectins; D001761:Bleomycin; D014212:Tretinoin; D005047:Etoposide; D002945:Cisplatin