Clinical Cancer Research, Vol 3, Issue 6 931-937, Copyright © 1997 by American Association for Cancer Research

ARTICLES

Synergistic antitumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo

DJ Lindner, EC Borden and DV Kalvakolanu
University of Maryland Cancer Center, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

Solid tumors are relatively resistant to growth inhibition by IFNs. To enhance sensitivity, we assessed combinations of IFNs with all-trans-retinoic acid (RA). Antiproliferative studies in vitro suggested that the growth of three human breast carcinomas (MCF-7, MDA-MB-231, and MDA-MB-468), an ovarian carcinoma (NIH-OVCAR-3), and a malignant melanoma (SK-MEL-1) was inhibited to a greater degree by combination treatment with human IFN-beta and RA compared to single agents. Some of these cell lines were resistant to 10-100 IU/ml human IFN-alpha2b or IFN-beta or to 0.1-1.0 microM RA. Growth was inhibited significantly by combinations of IFNs and RA in all cell lines tested, and in some cases, cytotoxicity was observed. Sequential treatment of MCF-7 cells with RA followed by IFN-beta was more effective at inhibiting growth than treatment with IFN-beta followed by RA, suggesting that RA modulated the anticellular response of IFN-beta rather than the converse. In nude mice, the growth of MCF-7 and NIH-OVCAR-3 tumors was suppressed completely when combination treatment was started 2 days after tumor inoculation. Established, 6-week-old NIH-OVCAR-3 tumors underwent regression when treated with the combination of IFN-beta and RA but not with single-agent therapy. Together with our recent studies that demonstrated enhancement of IFN-stimulated gene expression by RA pretreatment in IFN-resistant cells, these data suggest that combination treatment with RA and IFNs may increase IFN-stimulated gene expression in IFN-resistant tumors, leading to augmented antitumor effects.

This article has been cited by other articles:

				S. Kalakonda, S. C. Nallar, P. Gong, D. J. Lindner, S. E. Goldblum, S. P. Reddy, and D. V. Kalvakolanu Tumor Suppressive Protein Gene Associated with Retinoid-Interferon-Induced Mortality (GRIM)-19 Inhibits src-Induced Oncogenic Transformation at Multiple Levels Am. J. Pathol., October 1, 2007; 171(4): 1352 - 1368. [Abstract] [Full Text] [PDF]

				S. Kalakonda, S. C. Nallar, D. J. Lindner, J. Hu, S. P. Reddy, and D. V. Kalvakolanu Tumor-Suppressive Activity of the Cell Death Activator GRIM-19 on a Constitutively Active Signal Transducer and Activator of Transcription 3 Cancer Res., July 1, 2007; 67(13): 6212 - 6220. [Abstract] [Full Text] [PDF]

				K. Fan, M. Zhou, M. K. Pathak, D. J. Lindner, C. Z. Altuntas, V. K. Tuohy, E. C. Borden, and T. Yi Sodium Stibogluconate Interacts with IL-2 in Anti-Renca Tumor Action via a T Cell-Dependent Mechanism in Connection with Induction of Tumor-Infiltrating Macrophages J. Immunol., November 15, 2005; 175(10): 7003 - 7008. [Abstract] [Full Text] [PDF]

				Y. Takemoto, H. Yano, S. Momosaki, S. Ogasawara, N. Nishida, S. Kojiro, T. Kamura, and M. Kojiro Antiproliferative Effects of Interferon-{alpha}Con1 on Ovarian Clear Cell Adenocarcinoma In vitro and In vivo Clin. Cancer Res., November 1, 2004; 10(21): 7418 - 7426. [Abstract] [Full Text] [PDF]

				G. Huang, H. Lu, A. Hao, D. C. H. Ng, S. Ponniah, K. Guo, C. Lufei, Q. Zeng, and X. Cao GRIM-19, a Cell Death Regulatory Protein, Is Essential for Assembly and Function of Mitochondrial Complex I Mol. Cell. Biol., October 1, 2004; 24(19): 8447 - 8456. [Abstract] [Full Text] [PDF]

				J. Zhang, J. Yang, S. K. Roy, S. Tininini, J. Hu, J. F. Bromberg, V. Poli, G. R. Stark, and D. V. Kalvakolanu The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3 PNAS, August 5, 2003; 100(16): 9342 - 9347. [Abstract] [Full Text] [PDF]

				M. K. Pathak, D. Dhawan, D. J. Lindner, E. C. Borden, C. Farver, and T. Yi Pentamidine Is an Inhibitor of PRL Phosphatases with Anticancer Activity Mol. Cancer Ther., December 1, 2002; 1(14): 1255 - 1264. [Abstract] [Full Text] [PDF]

				T. Yi, M. K. Pathak, D. J. Lindner, M. E. Ketterer, C. Farver, and E. C. Borden Anticancer Activity of Sodium Stibogluconate in Synergy with IFNs J. Immunol., November 15, 2002; 169(10): 5978 - 5985. [Abstract] [Full Text] [PDF]

				D. J. Lindner, X. Ma, J. Hu, S. Karra, and D. V. Kalvakolanu Thioredoxin Reductase Plays a Critical Role in IFN Retinoid-mediated Tumor-Growth Control in Vivo Clin. Cancer Res., October 1, 2002; 8(10): 3210 - 3218. [Abstract] [Full Text] [PDF]

				T. Seo, D. Lee, Y. S. Shim, J. E. Angell, N. V. Chidambaram, D. V. Kalvakolanu, and J. Choe Viral Interferon Regulatory Factor 1 of Kaposi's Sarcoma-Associated Herpesvirus Interacts with a Cell Death Regulator, GRIM19, and Inhibits Interferon/Retinoic Acid-Induced Cell Death J. Virol., July 29, 2002; 76(17): 8797 - 8807. [Abstract] [Full Text] [PDF]

				X. Ma, J. Hu, D. J. Lindner, and D. V. Kalvakolanu Mutational Analysis of Human Thioredoxin Reductase 1. EFFECTS ON p53-MEDIATED GENE EXPRESSION AND INTERFERON AND RETINOIC ACID-INDUCED CELL DEATH J. Biol. Chem., June 14, 2002; 277(25): 22460 - 22468. [Abstract] [Full Text] [PDF]

				D. M. Shin, F. R. Khuri, B. Murphy, A. S. Garden, G. Clayman, M. Francisco, D. Liu, B. S. Glisson, L. Ginsberg, V. Papadimitrakopoulou, et al. Combined Interferon-Alfa, 13-cis-Retinoic Acid, and Alpha-Tocopherol in Locally Advanced Head and Neck Squamous Cell Carcinoma: Novel Bioadjuvant Phase II Trial J. Clin. Oncol., June 15, 2001; 19(12): 3010 - 3017. [Abstract] [Full Text] [PDF]

				D. M. Shin, L. Mao, V. M. Papadimitrakopoulou, G. Clayman, A. El-Naggar, H. J. C. Shin, J. J. Lee, J. S. Lee, A. Gillenwater, J. Myers, et al. Biochemopreventive Therapy for Patients With Premalignant Lesions of the Head and Neck and p53 Gene Expression J Natl Cancer Inst, January 5, 2000; 92(1): 69 - 73. [Full Text] [PDF]

				E. R. Hofman, M. Boyanapalli, D. J. Lindner, X. Weihua, B. A. Hassel, R. Jagus, P. L. Gutierrez, and D. V. Kalvakolanu Thioredoxin Reductase Mediates Cell Death Effects of the Combination of Beta Interferon and Retinoic Acid Mol. Cell. Biol., November 1, 1998; 18(11): 6493 - 6504. [Abstract] [Full Text]

				J. E. Angell, D. J. Lindner, P. S. Shapiro, E. R. Hofmann, and D. V. Kalvakolanu Identification of GRIM-19, a Novel Cell Death-regulatory Gene Induced by the Interferon-beta and Retinoic Acid Combination, Using a Genetic Approach J. Biol. Chem., October 20, 2000; 275(43): 33416 - 33426. [Abstract] [Full Text] [PDF]

				X. Ma, S. Karra, W. Guo, D. J. Lindner, J. Hu, J. E. Angell, E. R. Hofmann, S. P. M. Reddy, and D. V. Kalvakolanu Regulation of Interferon and Retinoic Acid-induced Cell Death Activation through Thioredoxin Reductase J. Biol. Chem., June 29, 2001; 276(27): 24843 - 24854. [Abstract] [Full Text] [PDF]