Study of inhibitory effects of an antiangiogenic somatostatin-camptothecin conjugate on laser-induced choroidal neovascularization in rats.

PURPOSE: To evaluate the ocular toxicity and efficacy of intravitreal camptothecin-somatostatin conjugate (JF-10-81), a somatostatin type 2 receptor-directed, antiangiogenic compound. METHODS: Part 1: New Zealand albino rabbits (except for controls) were injected intravitreally with conjugate at various concentrations. Preoperative and postoperative ocular examinations and electroretinography were performed until animals were killed for histology. Part 2: Long-Evans pigmented rats had choroidal neovascularization (CNV) induced by argon laser. One eye per animal was injected with concentration 10M (safe dose), whereas the other eyes were controls and received 30 microL of sterile water at different time intervals after laser application. Fluorescein angiography was performed at various time points to evaluate the lesions and confirm presence of CNV. Animals were euthanized. The eyes were immediately enucleated and prepared for histologic examination. RESULTS: Part 1: No clinical changes were seen in groups receiving 10(-8)M, 10(-7)M, 10(-6)M, and 10(-5) M of conjugate. Electroretinography showed decreasing b-wave amplitude in groups receiving 10(-4) M and 10(-3) M; cataracts also developed in these eyes. Part 2: Fluorescein angiography revealed that intravitreal injection of somatostatin conjugate JF-10-81 favorably affected the development of CNV when the treatment was performed at least 1 week after the laser application. These results were statistically significant. Histologic analysis results of eyes treated 2 weeks after laser application also showed significant benefit. CONCLUSIONS: Part 1: Camptothecin-somatostatin conjugate injected intravitreally appeared safe at concentrations of 10(-5)M or less. Part 2: Conjugate JF-10-81 at a concentration of 10(-5)M administered intravitreally 1 to 3 weeks after laser demonstrated statistically significant efficacy in the treatment of choroidal neovascularization.

The effect of drug dose and drug exposure time on the binding, internalization, and cytotoxicity of radiolabeled somatostatin analogs.

BACKGROUND: Creation of protease-resistant somatostatin analogs has allowed development of these peptides as clinically useful drugs. Widespread diagnostic use of radiolabeled somatostatin analogs has enhanced interest in the binding and intracellular distribution of these peptides. The degree of drug internalization and length of drug retention may be critical for drug-induced cytotoxicity. We hypothesized that the ability of a radiolabeled peptide to bind to a cell, be internalized, and induce cytotoxicity is proportional to both the radioligand concentration and the exposure time. MATERIALS AND METHODS: To test this hypothesis, somatostatin receptor-expressing cells (IMR-32) were incubated with (111)In-pentetreotide, a sst 2 preferring somatostatin analogue. Radioligand exposure time and/or concentration were varied. RESULTS: Prolonged exposure to a fixed concentration of radioligand resulted in progressive increases in whole cell binding and internalization over time. Cells exposed to a relatively fixed number of microCi-Hr yielded constant whole cell binding and internalization. Increasing the microCi-Hr resulted in a proportionate increase in binding. Cytotoxicity was also proportional to the dose of radiation regardless of whether the exposure was internalized radiation (microCi-Hr from (111)In-pentetreotide) or from external beam radiation (cGy). CONCLUSION: Both drug exposure time and drug concentration contribute to cell binding and cytotoxicity in this model and their relative contributions are inversely related.