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Influence of Retinoids on Growth and Metastasis of Hamster Melanoma in Athymic Mice¹

Department of Pharmacology [R. L. S., C. W. B.], Research Resources Center Biostatistics Facility [M. K. P.], University of Illinois School of Medicine at Chicago; Division of Surgical Oncology [M. K. P., C. W. B.], University of Illinois College of Medicine at Chicago, Cook County, and the West Side Veterans Administration Hospitals, the Hektoen Institute for Medical Research; and the Illinois Institute of Technology Research Institute [R. C. M.], Chicago, Illinois

The effects of 2-hydroxyethyl retinamide, N-(4-hydroxy-phenyl) all-trans-retinamide, and 13-cis-retinoic acid on the growth and metastasis of a malignant hamster melanoma cell line HM1-F5 was determined in a double blind study using 4- to 5-week-old male NIH Swiss and BALB/c derived athymic nu/nu mice. Mice were fed retinoids (0.75 and 1.0 or 1.5 mmol/kg diet) or a placebo diet ad libitum beginning on the day of s.c. inoculation of 5 x 10⁵ HM1-5 cells. Tumor incidence, latency, and growth rate were similar in both strains of mice. All placebo-treated mice had lung metastasis on the day of autopsy, although the total number of metastases was lower in NIH Swiss derived athymic mice. While mean tumor incidence and latency were not significantly altered by any retinoid treatment, tumor growth rate (volume) and final tumor weight were inhibited (P < 0.05) by 0.75 mmol/kg 13-cis retinoic acid and 1.5 mmol/kg N-(4-hydroxyphenyl) all-trans-retinamide. In contrast, at 1.0 or 1.5 mmol/kg diet, 2-hydroxyethyl retinamide had no significant effect on tumor growth rate. 13-cis retinoic acid, 0.75 mmol/kg, 2-hydroxyethyl, 1.0 mmol/kg, and N-(4-hydroxyphenyl), 1.0 mmol/kg significantly reduced the mean number of metastatic lesions in NIH Swiss derived mice, but N-(4-hydroxyphenyl) all-trans-retinamide also reduced metastatic incidence while 2-hydroxyethyl retinamide and 13-cis retinoic acid had no effect. A concentration of 1.5 mmol/kg diet of 2-hydroxyethyl and N-(4-hydroxyphenyl) all-trans-retinamide significantly reduced the overall number of gross lung metastases in BALB/c and Swiss mice, and mean number of metastases in Swiss mice. Analysis of correlation indicated that the inhibitory effect of high-dose N-(4-hydroxyphenyl) and 2-hydroxyethyl retinamide on metastasis was not associated with (independent of) any inhibitory effect on primary tumor invasiveness or growth rate. Our observations suggest that agents such as retinoids have an antimetastatic potential.

¹ Supported by National Cancer Institute Grants CA 31046 (C. W. B.), N01-CB-7420, and N01-CP-15742 (R. C. M.), the Louis Lerner Memorial Fund for Cancer Research, and the Fayette County Fund for Cancer Research.

² Present address: Emory University School of Medicine, Medical Research Service, VA Medical Center, 1670 Clairmont Road, Decatur, GA 30033.

³ To whom requests for reprints should be addressed, at Division of Surgical Oncology, University of Illinois College of Medicine at Chicago, 840 South Wood Street, Chicago, IL 60612.

Received 2/ 6/87. Revised 9/30/87. Revised 12/ 8/87. Accepted 12/ 9/87.