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Objective: The objective of this study was to compare the efficacy of photoimmunoconjugates with cationic and anionic molecular charges on intraperitoneal photoimmunotherapy of ovarian cancer xenografts in nude mice., Methods: The photosensitizer chlorin(e6) (c(e6)) was conjugated via a poly-l-lysine linker to the F(ab')(2) fragment of the murine anti-ovarian cancer monoclonal antibody OC125, resulting in a photoimmunoconjugate with a pronounced cationic charge. Alternatively, by succinylating the poly-l-lysine conjugate, a photoimmunoconjugate with a pronounced anionic charge was obtained. A murine model of ovarian cancer derived from intraperitoneal inoculation of NIH:OVCAR-5 cells was employed. The conjugate was injected intraperitoneally followed after 3 h by red light delivered through a fiber into the peritoneal cavity. These photoimmunotherapy treatments were repeated three times, and the results obtained with the anionic and cationic photoimmunoconjugates were compared with those obtained with free c(e6) and control. The extent of residual macroscopic disease and death from disease were the evaluable outcomes for tumoricidal and survival studies, respectively., Results: In contrast to other intraperitoneal photosensitizers, mice showed no systemic toxicity or morbidity from the treatment. In this initial study the mean residual tumor weights in all treatment groups ranged from 33 to 73 mg, as compared with 330 mg in untreated controls (P < 0.0001), and the response to the cationic conjugate was significantly better than that to the anionic conjugate or free c(e6) (P < 0.005). The median survival for mice treated with cationic photoimmunoconjugate was 41 days, compared with 35 days in controls (P = 0.009)., Conclusion: Photoimmunotherapy with a cationic photoimmunoconjugate produces results superior to those obtained with an anionic conjugate, and further optimization of the treatment regimen may lead to a potential treatment for advanced ovarian cancer., (Copyright 2000 Academic Press.)

A new xenograft model for human epithelial ovarian carcinoma, with extensive intraperitoneal (i.p.) carcinomatosis as the predominant disease manifestation, is described. Cells from the established NIH:OVCAR-5 cell line were injected i.p. into 6- to 8-week-old Swiss nude mice. Comparative analyses between cells cultured in vitro and tumor cells derived ex vivo were performed to assess histologic features, immunohistochemical cell markers, hormonal receptor expression, adhesion to extracellular matrix molecules and chromosomal constitution. Macroscopically, the extent of tumor development appeared to be site-dependent and tumor cell survival was dose-dependent. Advanced disease was characterized by extensive solid tumor burden and ascites with parenchymal invasion, lymphatic metastases and vascular dissemination. Individual tumor nodules exhibited developing neovasculature characterized by the absence of mature basement membrane. Despite some histologic loss of cellular differentiation in advanced disease, antigenic expression was preserved, distinguishing these cells as epithelial in origin. Karyotyping of tumor cells demonstrated multiple numeric and structural chromosomal abnormalities. Serum and ascites CA 125 levels were consistently elevated only in tumor-bearing mice. This new murine model closely resembles the aggressive disease process of human epithelial ovarian carcinoma, in which the efficacy of i.p. and systemic therapeutic modalities can be investigated.

The objective of this investigation was to determine the efficacy of i.p. photodynamic therapy (PDT) against solid, multifocal ovarian carcinoma using a newly described NIH:OVCAR-5 induced murine model. PDT was initiated when diffuse microscopic disease and small multifocal tumor nodules were present, similar to the extent of residual carcinoma that may persist clinically after laparotomy and tumor debulking. The photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA), was administered in a dose of 0.25 mg/kg body weight i.p. 90 min prior to light exposure. An argon-pumped dye laser was used to deliver low intensity light (20 J) i.p. through a cylindrically diffusing fiberoptic tip. Treatment regimens consisted of a series of three to five treatments at 3-7 day intervals, with the extent of macroscopic disease or death from disease being the evaluable outcome parameters for tumoricidal and survival studies, respectively. The mean tumor burden at necropsy for treated animals was 0.034 +/- 0.014 g compared to 0.379 +/- 0.065 g in untreated controls (P<0.001). Survival studies were initiated in two groups at day 7 and day 14 following cell inoculation. The first group received either three or five treatments at 5-day intervals, and both had a significant increase in median survival compared to untreated controls (57 and 53 days, respectively, compared to 43 days, P<0.05). The second group was treated every 7 days until death and also had a significant survival advantage over controls (57 days compared to 47 days, P<0.05). These studies suggest that benzoporphyrin derivative mono acid ring A-mediated PDT is a feasible, well-tolerated, experimental treatment approach that elicits a tumoricidal response against diffuse, solid i.p. disease in tumor-bearing mice, with concomitant prolongation of survival and needs careful optimization.