EXPERIMENTAL BASIS OF CANCER COMBINATION CHEMOTHERAPY WITH RETINOIDS, CYTOKINES, 1,25-DIHYDROXYVITAMIN D-3, AND ANALOGS

Retinoids, cytokines as well as 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] and analogs possess properties known to contribute potentially to cancer chemopreventive and chemotherapeutic effects. They induce cell differentiation, inhibit cell proliferation, suppress expression of viral oncogenes, and inhibit angiogenesis necessary for tumor growth. Since clinical combination chemotherapy of cytotoxic agents has proven superior to monotherapy, this modality might also be useful for other classes of antitumor drugs. A series of retinoids, such as all-trans-, 13-cis-, 9-cis retinoic acid, and acitretin, cytokines, 1,25(OH)(2)D-3, and analogs have been investigated in model systems of differentiation, proliferation, viral oncogenes, and angiogenesis. The three classes of compounds have common effects but nevertheless show a variance depending on the particular representative of each class. Combination of compounds of the different classes led in the various models to a higher efficacy compared with the compounds given alone. Cytokines such as IFN alpha, IFN gamma, G-CSF, TNF alpha, IL-1, and IL-4 markedly potentiate the differentiation-inducing effect of retinoids. Cytokines as well as retinoids combined with 1,25(OH)(2)D-3 and analogs synergistically enhanced differentiation induction in human transformed hemopoietic cell lines. On a series of human transformed epithelial cell lines a panel of cytokines, such as IFN alpha, IFN gamma, TNF alpha, TGF beta, and EGF acted synergistically with retinoids on inhibition of proliferation. This was also observed by combining retinoids with 1,25(OH)(2)D-3 and analogs. Retinoids as well as interferons alpha and gamma have the capacity to suppress the oncogene expression of human papilloma viruses which are involved in induction and growth of certain malignancies such as cervical cancer. All-trans-, 13-cis-, 9-cis retinoic acid, and acitretin as well as IFN alpha inhibited the formation of newly formed blood vessels induced by injection of HPV harboring, tumorigenic cell lines into Balb/C mice. The combination of retinoids with IFN alpha was more efficacious in inhibiting angiogenesis than a retinoid or IFN alpha given alone. Since there is evidence that cell differentiation, cell proliferation, viral oncogene expression as well as angiogenesis play a role in tumor induction and/or progression of tumor growth, retinoids, cytokines, as well as 1,25(OH)(2)D-3 and analogs may be useful in chemoprevention and chemotherapy of neoplasms. Based on the superior effect of combinations compared with administration of single compounds of these three classes under experimental conditions there is hope that also clinical application of combination treatment might bring us a step forward in chemoprevention and chemotherapy of cancer. This has already been proven in a very limited number of clinical trials. (C) 1994 Wiiey-Liss, Inc.