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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.

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.

ABSTRACT: Indium In 111 pentetreotide imaging of neuroendocrine tumors that overexpress somatostatin receptors has become standard for localization of these tumors. This radioligand is internalized into the cell and can induce receptor-specific cytotoxicity by emission of Auger electrons. We hypothesized that high-dose [sup 111]In-pentetreotide could be therapeutic in patients with somatostatin receptor-expressing tumors. Our 35-year-old patient had atypical carcinoid tumor metastatic to cervical, supraclavicular, mediastinal, and mesenteric lymph nodes and to the liver and bone. Chemotherapy had stabilized the disease but with severe gastrointestinal side effects. After a diagnostic [sup 111]In-pentetreotide therapy to selectively target somatostatin receptor-expressing tumor cells. The disease was stable for approximately 14 months. The patient had two additional courses of [sup 111]In-pentetreotide therapy (360 mCi each). She died of the disease approximately 18 months after initiation of [sup 111]In-pentetreotide scan, the patient was given eight courses (180 mCi each) of [sup 111]In-pentetreotide therapy. [ABSTRACT FROM AUTHOR]