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Combination Chemotherapy and Photodynamic Therapy with N-(2-Hydroxypropyl)methacrylamide Copolymer-bound Anticancer Drugs Inhibit Human Ovarian Carcinoma Heterotransplanted in Nude Mice¹

C. Matthew Peterson², Jing Ming Lu, Yongren Sun, C. Anthony Peterson, Jane-Guo Shiah, Richard C. Straight and Jindich Kopeek

Departments of Obstetrics and Gynecology [C. M. P., C. A. P.], Bioengineering and Pharmaceutics and Pharmaceutical Chemistry [J-G. S., J. K.], and Surgery [Y. S., R. C. S.], and John A. Dixon Laser Institute [C. M. P., Y. S., R. C. S.], University of Utah, Salt Lake City, Utah 84132; Veterans Administration Medical Center, Salt Lake City, Utah 84148 [C. M. P., R. C. S.]; and Department of Obstetrics and Gynecology, China Medical University-Shenyang Branch, Shenyang, People's Republic of China [J. M. L.]

This study characterizes the efficacy and toxicity of: (a) free Adriamycin and N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-Adriamycin conjugate (P-A); (b) free and HPMA copolymer-meso-chlorin e₆ monoethylene diamine disodium salt (Mce₆) conjugate (P-C) and light-induced photodynamic therapy; and (c) combinations of the HPMA copolymer conjugates (P-A and P-C) in the destruction of human epithelial ovarian carcinoma heterotransplanted in the nude mouse (OVCAR-3). Eight-week-old female nu/nu mice were injected in both flanks with 0.04–0.05 cm³ OVCAR-3 solid tumor dispersed in media. When bilateral tumors reached a minimum volume of 0.18 cm³ (one axis, 2.0-mm minimum) and demonstrated consistent growth, the experiments were initiated. Drugs were given i.v. unless otherwise noted. Tumor-bearing mice were allocated to the following protocols: (a) Adriamycin at 1 mg/kg, P-A at 30 mg/kg (2.2 mg/kg Adriamycin equivalent), and controls (n = 6 each); (b) Mce₆ and light (2 h after administration; 650 nm light for 15 min to deliver 220 J/cm²) at 1.25, 2.5, 5, and 10 mg/kg (n = 6 each), 2.5 mg/kg i.p. (n = 4), and controls (n = 6); (c) P-C at 12.5, 25, and 75 mg/kg (1.5, 2.9, and 8.7 mg/kg Mce₆ equivalent, respectively) with light (18 h after administration; 650 nm light for 15 min to deliver 220 J/cm²), P-C at 25 mg/kg (2.9 mg/kg Mce₆ equivalent) with no light administration, and controls (n = 7 each); and (d) a combination of P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) and P-C (12.5 and 75 mg/kg, 1.5 mg/kg and 8.7 mg/kg Mce⁶ equivalent, respectively) with and without light (n = 7 each; 18 h after administration; 650 nm light for 15 min to deliver 220 J/cm²) and controls (n = 12). Tumor volumes and animal weights were assessed for significant differences from the treated and control groups by Student's t test. Adriamycin (1 mg/kg) and P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) caused less than a 10% weight loss, and treated tumor volumes (day 10–32) were significantly less than those of controls (all P < 0.045). Mce₆ (2.5–10 mg/kg i.v.), caused tumor regression in 80% of tumors and a shock syndrome in 17–83%. i.p. dosing (2.5 mg/kg) was uniformly fatal. Mce₆ at 1.25 mg/kg did not show reproducible efficacy. P-C with light (25 and 75 mg/kg, 2.9 and 8.7 mg/kg Mce₆ equivalent, respectively) demonstrated significant tumor destruction (P < 0.003) but not complete ablation. The combinations of P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) plus P-C (12.5 and 75 mg/kg; 1.5 mg/kg and 8.7 mg/kg of Mce₆ equivalent, respectively) with light resulted in tumor volumes that were significantly less than control tumor volumes and the tumor volumes of mice receiving either P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) or P-C with light (12.5 or 75 mg/kg, 1.5 or 8.7 mg/kg Mce₆ equivalent, respectively) alone (all P < 0.02). P-C (75 mg/kg, 8.7 mg/kg Mce₆ equivalent) added to P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) resulted in complete tumor ablation. Free Mce₆ demonstrates a narrow margin of safety, which is extended by incorporation into HPMA copolymers. P-A demonstrates safety and efficacy in vivo. The combined chemotherapy and photodynamic therapy of P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) with P-C and light (12.5 and 75 mg/kg 1.5 and 8.7 mg/kg Mce₆ equivalent, respectively) was nontoxic and allowed us to attain a significant improvement in tumor cures than those obtained by P-A or P-C with light alone.

¹ This research was supported in part by NIH National Cancer Institute Grant CA51578 and by the Department of Veterans Affairs Medical Research Program.

² To whom requests for reprints should be addressed, at Department of Obstetrics and Gynecology, University of Utah School of Medicine, 50 North Medical Drive, Salt Lake City, UT 84132. Phone: (801) 581-6880; Fax: (801) 585-5146; E-mail: peterson@msscc.med.utah.edu.

Received 9/ 7/95. Accepted 7/ 2/96.

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