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Inhibition of Human Melanoma Growth by Prostaglandin A, D, and J Analogues¹

Cancer Center Division, University of Arizona, College of Medicine, Tucson, Arizona 85724 [M. D. B., C. F.], and AlCHl Cancer Center, Department of Internal Medicine, Chikussa-ku, Nagoya, Japan 464 [M. F.]

The relative inhibitory potency of prostaglandin A (PGA) and prostaglandin J₂ (PGJ₂) analogues compared to prostaglandin A₁ (PGA₁) was determined in a clonogenic assay system. Three human melanoma cell strains (C8146A, C8146C, and C8161), a human melanoma cell line (M1RW5) and a human neuroblastoma cell line (IMR-32) were used. Prostaglandin analogues were screened in the clonogenic assay system and the dose effect curves were analyzed by linear regression utilizing the median effect relationship. The computer-generated 50% and 95% inhibitory doses showed that 15-deoxyl-16-hydroxyl-16-vinyl-prostaglandin A₂ (DHV-PGA₂) was from two- to three-fold more active than PGA₁ in inhibiting the clonogenic growth of human melanoma cells. Based on the 50% inhibitory dose, PGJ₂ and its analogues were from two to five times more potent than PGA₁. The ¹²- and ^12,14-PGJ₂ were the most potent of the prostaglandins tested. However, the 95% inhibitory dose for prostaglandin D₂ (PGD₂), PGJ₂ and its analogues against neuroblastoma did not show any enhancement in activity in comparison to PGA₁, suggesting that some tumor specificity in the activity of these analogues may be signified by the neuroblastoma data.

Prostaglandins which contained a fluoride substitution at position 11 were also tested for activity. As we previously observed with other analogues which did not contain an ,ß-unsaturated carbonyl group in the cyclopentane ring, 9ß,15-dihydroxy-11ß-fluoroprosta-5-cis-13-trans-dienoic acid and 9,15-dihydroxy-11ß-fluoroprosta-5-cis-13-trans-dienoic acid did not inhibit the clonogenic growth of human melanoma cells.

Administration s.c. to established human melanoma tumors growing in athymic nude mice caused a significant growth inhibition. The treatment schedules ranged from 1 to 8 days. Injection s.c. of PGA₁ at a dose of 40 mg/kg/day resulted in a 20% suppression in tumor growth. Higher doses (100 and 200 mg/kg/day) effected an 80% reduction in tumor growth. The higher doses were associated with reversible toxicities, diarrhea and skin inflammation. Administration of DHV-PGA₂ at a dose of 20 mg/kg/day resulted in 40% reduction in tumor growth. The increased in vivo potency of DHV-PGA₂ corresponds to the results obtained in the clonogenic assay system.

¹ This investigation was supported by USPHS Grant CA34689 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 11/ 7/85. Revised 2/12/86. Accepted 2/14/86.

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