© 1995 Oxford University Press
research-article |
Comparative Skin Phototoxicity in Mice with Two Photosensitizing Drugs: Benzoporphyrin Derivative Monoacid Ring A and Porfimer Sodium (Photofrin)
*Medical Research Division, American Cyanamid Company Pearl River, New York 10965
Quadra Logic Technologies, Inc. Vancouver, British Columbia, Canada V5Z 4H5
Received May 13, 1994; accepted June 3, 1994
Benzoporphyrin derivative monoacid ring A (BPD-MA) and Photofrin (porfimer sodium) are photodynamic anticancer agents. The chemical structures of the two regioisomers of BPD-MA are 9-methyl trans-{±)-18-ethenyl-4,4
-dihydro-3,4-bis(methoxycarbonyl)-4,8,14,19-tetramethyl-4,4-dihydro-3, 4-bis (methoxycarbonyl)-4, 8,14,19-tetramethyl-23H, 25H-benzo(b)porphine-9,13-dipropanoate and 13-methyl-trans-(±)-18-ethenyl-4,4-dihydro-3,4-bis(methoxycarbonyl)-4,8, 14,19-tetramethyl-23H,25H-benzo(b)porphine-9,13-dipropanoate. Photofrin (a registered trademark of American Cyanamid Co.) is a polyporphrin oligomer containing ester and ether linkages. The ability of BPD-MA or Photofrin to cause skin phototoxicity was investigated in mice exposed to simulated sunlight (light) 3, 24, or 48 hr after receiving a single intravenous injection of vehicle or 2, 10, or 20 mg/kg of BPD-MA or Photofrin. The data were from two studies conducted using male and female CD1 mice (
7 weeks old). The hair of the dorsal thoracic area was clipped 24 hr prior to exposure to light. Mice were exposed to light for 5 min. The clipped area of skin was the primary site for the evaluation of phototoxicity. Mice were observed for 2 weeks after treatment. There were no significant findings in controls or in mice given 2 mg/kg of BPD-MA. When mice were exposed to light 3 hr after dosing, both BPD-MA (10 or 20 mg/kg) and Photofrin (2, 10 or 20 mg/kg) caused phototoxicity. Death occurred in all mice given 20 mg/kg of BPD-MA or Photofrin, and in the majority of mice given 10 mg/kg of Photofrin. In surviving mice, the skin of the back reacted by forming a large area of eschar (scab). When mice were exposed to light 24 or 48 hr after administration of BPD-MA or Photofrin, significant phototoxicity (browned skin and eschar formation) was observed only in the mice given Photofrin. The data suggest that in mice BPD-MA causes substantial tissue injury when photoactivated 3 hr after administration, but that the potential for phototoxicity is essentially gone after 24 hr. In contrast, phototoxicity was elicited in the skin of mice exposed to simulated sunlight 3, 24, and 48 hr after injection of Photofrin.