The effect of retinoic acid on chemosensitivity of PA‐1 human teratocarcinoma cells and its modulation by an activated N‐ras oncogene

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Abstract
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 10−6M 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.