Activity of ALRT 1550, a new retinoid, with interferon-gamma on ovarian cancer cell lines.
Retinoids have been shown to be effective regulators of cell proliferation and differentiation in many human cancers. The major biologic activity of the retinoids is mediated by two families of nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). ALRT 1550 is one of the most potent RAR selective retinoids discovered to date, with 10-100 times more activity than ATRA in competitive binding and cotransfection assays and 300 times more inhibiting activity against proliferation of cervical carcinoma cell. To evaluate the role of ALRT 1550 in ovarian cancer, the growth inhibitory activity of ALRT 1550 was determined in the ATRA-resistant ovarian cancer cell line SKOV-3 and ovarian cancer cell line 2774 after exposure to concentrations of 0.1, 1, 2.5, 5, and 10 microM for 7 days. SKOV-3 showed 51%, 53%, and 68% cell growth inhibition after treatment with ALRT 1550 at concentrations of 2.5, 5, and 10 microM, respectively, and the 2774 cell line showed 46% inhibition after treatment at 10 microM. Because interferon (IFN)-gamma was found to synergistically amplify the growth inhibition of retinoids in cultured breast cancer cells, we investigated the combination of ALRT 1550 with IFN-gamma in two ovarian cancer cell lines. ALRT 1550 (5 microM) in combination with IFN-gamma at a concentration of 500 U/ml inhibited cell growth of SKOV-3 by as much as 81% (CI = 1.88). This is a 28% greater effect than with ALRT alone. Cell line 2774 showed a 69% cell growth inhibitory effect with ALRT 1550 (5 microM) in combination with IFN-gamma at a concentration of 1000 U/ml (CI = 1.03). ALRT 1550 and IFN-gamma may act synergistically in the SKOV-3 ovarian cancer cell line and additively in the 2774 cell line. In conclusion, ALRT 1550 may be a promising drug with a high biologic modulating activity against ovarian cancer. In combination with IFN-gamma, additive and perhaps synergistic effects may be seen in some ovarian cancer cell lines. Combining these two biologic modifiers for the treatment of ovarian cancer may lower the effective dose of the retinoids, thus decreasing their side effects.
Hu
Wei
W
Department of Gynecologic Medical Oncology, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. weihu@mdanderson.org
Verschraegen
C F
CF
Wu
W G
WG
Nash
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M
Freedman
R S
RS
Kudelka
A
A
Kavanagh
J J
JJ
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012176:Retinoids / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D000097768:Retinoic Acid Receptor gamma
D000970:Antineoplastic Agents; D007371:Interferon-gamma; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D000097768:Retinoic Acid Receptor gamma; C100800:ALRT 1550