Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: a rationale for combination therapy with chemotherapeutic agents.
We have previously shown that beta-all trans retinoic acid (RA) inhibits macrocellular growth of a multicellular tumor spheroid model for squamous carcinoma, as measured by spheroid size, but allows for continuing DNA synthesis and cell cycle progression, the two being reconciled by a cell death effect. DNA synthesis in the presence of growth inhibition suggested a rationale for examining combination chemotherapy with RA-inhibited cells. To this aim, we have extended this observation to a series of 8 squamous carcinoma cell lines. Cells were treated with 1 microM RA for 7 days and cell growth parameters monitored. Although growth inhibition ranged from 0% (A431) to approx. 80% (MDA 886Ln), [3H]-thymidine incorporation (cpm/microgram protein) and percent S-phase (by flow cytometry) in 7-day RA-treated cells was equal or higher than in their control vehicle-treated cells in 7/8 SCC cell lines. Thus RA-induced growth inhibition is not just cytostasis. Combination therapy was examined with MDA 886Ln, MDA 686Ln, 1483 and A431 cells pre-treated for 7 days with 1 microM RA followed by cisplatin or 5-fluorouracil treatment. An increased effectiveness for the combination was shown using 5-day tetrazolium dye (MTT) growth assays when cells were growth-inhibited by RA. Computerized analysis of data using median-effect and isobologram techniques indicated that the interaction of RA with these chemotherapeutic agents was synergistic. With squamous carcinoma, RA treatment inhibits growth while allowing for continuing DNA synthesis, and these RA-treated, growth-inhibited cells exhibit increased sensitivity to chemotherapeutic agents.
Sacks
P G
PG
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Harris
D
D
Chou
T C
TC
D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000633:toxicity*; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000633:toxicity*; D006258:Head and Neck Neoplasms; D006801:Humans; D016196:S Phase / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D014212:Tretinoin; D002945:Cisplatin; D005472:Fluorouracil