Combination chemotherapy and photodynamic therapy with N-(2-hydroxypropyl) methacrylamide copolymer-bound anticancer drugs inhibit human ovarian carcinoma heterotransplanted in nude mice.
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 animals weights were assessed for significant differences from the treated and controls 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.
Peterson
C M
CM
Department of Obstetrics and Gynecology, University of Utah, Salt Lake City 84132, USA. peterson@msscc.med.utah.edu
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Sun
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Peterson
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Straight
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Kopecek
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D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002455:Cell Division / Q000187:drug effects; D002735:Chlorophyllides; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D004337:Drug Carriers; D005260:Female; D006801:Humans; D008689:Methacrylates / Q000008:administration & dosage*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010778:Photochemotherapy; D011166:Porphyrins / Q000008:administration & dosage* / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000494:pharmacology; D014183:Transplantation, Heterologous
D000903:Antibiotics, Antineoplastic; D002735:Chlorophyllides; D004337:Drug Carriers; D008689:Methacrylates; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; C062985:phytochlorin; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate