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Isobolographic Assessment of the Interaction Between Adriamycin and Photodynamic Therapy With Meso-Chlorin E6 Monoethylene Diamine in Human Epithelial Overian Carcinoma (OVCAR-3) In Vitro

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology; the John A. Dixon Utah Laser Institute and the Department of Veterans Affairs Medical Research Program; Department of Bioengineering and of Pharmaceutics and Pharmaceutical Chemistry, Univerity of Utah. Salt Lake City, Utah; Division of Reproductive Endocrinology, Department of Bosterics and Gynecology, University of Utah School of Medicine, 50 North Medicial Drive, Salt Lake City, UT 84132

Jing Ming Lu, MD

Zhong-wei Gu, MS

Jane-Guo Shiah, BS

Kevin Lythgoe, MD

Anthony C. Peterson

Richard C. Straight, PhD

Jindich Kope, PhD, DSc

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology; the John A. Dixon Utah Laser Institute and the Department of Veterans Affairs Medical Research Program; Department of Bioengineering and of Pharmaceutics and Pharmaceutical Chemistry, Univerity of Utah. Salt Lake City, Utah

Objective: Considering the differing mechaniisms of cytotoxicity produced by adriamycin and the photosensitizer meso-chlorin e₆ monoethylene diamine (Mce₆) with light, the interaction of these agants in combination on human ovarian epithelial carcinoma (OVCAR-3 in vitro) was evaluated by dose and effect addition isobole analysis.

Methods: Mitochondrial respiration via the 3-(4,5-dimethyl thiazeol-2 yl)-2,5-diphenyl tetrazolium bromide cleavage assay (MTT) and reproductive capacity via the tritiated thymidine incorporation assay (TI) were assessed 72 and 144 hours after exposure to adriamycin, Mce₆, and light (650 nm), and to their combinations, in OVCAR-3 cells grown in vitro (20,000 cells per well).

Results: In the majority of assays, reproductive capacity was more sensitive to the drug(s) than was mitochondrial respiration (2-10X). Dose-addition isobole analysis showed synergy for the combination of 50% median effective dose (ED₅₀) adriamycin with 50% ED₅₀Mce₆/light in all assays (all P .027). Antagonism was noted with the combination 25% ED₅₀ adriamycin with 75% ED₅₀ Mce₆/light. Additivity and synergy were the predominant interactions for 75% ED₅₀ adriamycin with 25% ED₅₀ Mce₆/light by dose-addition isobole analyses. Effect-addition isoboles showed a preominance of synergy, particularly for the combination 50% ED₅₀ adriamycin with 50% ED₅₀Mce₆/light.

Conclusion: Synergy and additivity are the primary in vitro interactions for the combination of adriamycin and Mce₆/light in the dosage range tested. Reproductive capacity is more sensitive to the these agents than in mitochondrial respiration.

Key Words: Adtriamycin • Doxorubicin • meso-chlorin e6 monoethylene diamine disodium salt • Mce6 • isobologram • ovarian cancer • photodynamic therapy

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