Medroxyprogesterone acetate(MPA) enhances the cytotoxicity of VCR,ADR and Ara C in human pulmonary carcinoma cells in vitro.
Department of Thoracic Surgery, Miyagi cardiovascular and respiratory center, Miyagi, Japan
AIM: During studies aimed at finding useful modulators for clinically used anticancer drugs, we have found that indomethacin is an effective modulator on VCR and ADR cytotoxicity in human pulmonary adenocarcinoma cells as previously reported. In the present study, we examined the combined effect of various steroid hormones and anticancer drugs against human pulmonary carcinoma cell lines by MTT assay. Methods: We examined the drug sensitivity of 12 pulmonary carcinoma cell lines in the presence of two drugs, an anticancer drug and an steroid hormone, for 72 hours by the MTT assay with 96 well plates. Anticancer drugs used for screening test were; cyclophosphamide(CPM), carboquone(CQ), mitomycin C(MMC), adriamycin(ADR), 5-fluorouracil(5FU), vindesine (VDS), cisplatin (CDDP), carboplatin (CBDCA), cytarabine(Ara C), methotrexate(MTX), etoposide (VP-16) and vincristine (VCR). Steroid hormones examined as modulators to anticancer drugs were; betamethasone, corticosterone, deoxycorticosterone acetate, hydrocortisone, prednisolone, spinolactone, methltestosterone, testosterone, estriol, norethisterone, progesterone, medroxy- progesterone acetate (MPA), cortisone and 17α-hydroxy progesterone. Results: As a result of screening tests, MPA was the most effective modulator at relatively lower concentration, resulting in over 2-fold increases in cytotoxicity of VCR in combination with 500ng/ml MPA which was the serum consentration in ordinary clinical usage as compared with that produced by VCR alone. In the pulmonary adenocarcinoma cell line 76-2, the IC50 for single agent VCR was 1.68±0.18(SE)ng/ml. When 500 ng/ml of MPA is added to the assay, the IC50 for VCR decreased to 0.71±0.1(SE)ng/ml which represents a 2.37-fold decrease. In another adenocarcinoma cell line 77-4, the IC50 for VCR alone and VCR in combination with 500 ng/ml MPA were 3.10±0.28 and 1.03±0.1(SE)ng/ml respectively, which represents a 3.01-fold decrease. Each of the 12 anticancer drugs was studied in combination with MPA, VCR was the most effective anti-cancer drug in combination with MPA, followed by ADR and Ara C. Therefore, we next examined the modulating effect of MPA to VCR against other 10 human pulmonary carcinoma cell lines with different histological types. Of these 10 human pulmonary carcinoma cell lines, 8 showed a potent combined effect(over 2 fold increase of sensitivity ) of VCR and MPA. The mean MI was 2.7 fold. Conclusions: Our studies indicate that clinically achievable concentrations of MPA may be useful in modulating VCR, ADR and Ara C resistance in human pulmonary carcinoma cells, so that combined use of these anticancer drugs and MPA may be of potential clinical significance in the treatment of lung cancer
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in poster session 991 (Synergistic therapies).