title: Synergistic antitumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo.
abstract: 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.
authors.affiliation: University of Maryland Cancer Center, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lindner
authors.forename: E C
authors.initials: EC
authors.lastname: Borden
authors.forename: D V
authors.initials: DV
authors.lastname: Kalvakolanu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D003131:Combined Modality Therapy; D004357:Drug Synergism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000627:therapeutic use* / Q000633:toxicity*; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D011960:Receptors, Estrogen / Q000032:analysis; D011994:Recombinant Proteins / Q000627:therapeutic use / Q000633:toxicity; D014212:Tretinoin / Q000627:therapeutic use* / Q000633:toxicity*; D014407:Tumor Cells, Cultured
chemical_list: D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D000068576:Interferon beta-1b; D004958:Estradiol; D014212:Tretinoin; D016899:Interferon-beta; D000068556:Interferon beta-1a