Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: A rationale for combination therapy with chemotherapeutic agents

Abstract

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.

Multifactorial mechanism for the potentiation of cisplatin (CDDP) cytotoxicity by all-trans retinoic acid (ATRA) in human ovarian carcinoma cell lines

“…This effect on ovarian carcinoma cell proliferation was only observed when ATRA was added before CDDP and for a duration corresponding to the doubling time of the different ovarian adenocarcinoma cells. For NIHOVCAR3 cells, the optimal effect was observed at 48 h. These results are in line with those previously reported for small-cell lung cancer (Doyle et al, 1989), for an ovarian teratocarcinoma (Le Ruppert et al, 1992), for a murine embryonal carcinoma cell line (Guchelaar et al, 1993) and for epidermoid carcinoma (Sacks et al, 1995). Taken together, these observations suggest that ATRA induces a cascade of events facilitating CDDP cytotoxicity.…”

“…Furthermore, the combination of ATRA and CDDP has been reported to be beneficial in the treatment of head and neck tumours (Sacks et al, 1995). Fenretinide, a synthetic retinoid, has also been shown to enhance the anti-tumour activity of CDDP against a human ovarian carcinoma cell line xenografted in nude mice (Formelli et al, 1993).…”

Retinoid metabolism and all-trans retinoic acid-induced growth inhibition in head and neck squamous cell carcinoma cell lines

“…In vitro, variation in growth inhibition after exposure of HNSCC to all-trans RA has been reported (Jetten et al, 1990;Sacks et al, 1995), and thus far this variation cannot be explained (Zou et al, 1994). The aim of this study was to investigate the presence or absence of a variation in retinoid metabolism between HNSCC cell lines and whether this is related to the degree of growth inhibition by all-trans RA.…”

Potentiation of cytotoxicity by combination of imatinib and chlorimipramine in glioma

“…Results were considered significant with p<0.0005, p<0.001, p<0.01 and p<0.05. Synergy was determined as described previously (31)(32)(33). By this method, synergism was detemined using the following equation: 2 , where D 1 is the tested concentration of IM used in combination with CIMP, D 2 is the tested concentration of CIMP used in combination with IM, DX is the concentration of IM alone and (DX) 2 is the concentration of CIMP alone.…”