Combining high selectivity of replication with fiber chimerism for effective adenoviral oncolysis of CAR-negative melanoma cells

Oncolytic adenoviruses constitute a new and promising tool for cancer treatment that has been rapidly translated into clinical trials. However, minimal or absent expression of the adenovirus serotype 5 (Ad5) receptor CAR (coxsackievirus and adenovirus receptor) on cancer cells represents a major limitation for Ad5-based oncolysis. Here, we report on the resistance of CAR-negative primary melanoma cells to cell killing by wild-type Ad5 (Ad5wt) even after high titer infection, thus underlining the need for tropism-modification of oncolytic adenoviruses. We engineered a new generation of oncolytic adenoviruses that exhibit both efficient target cell infection by swapping Ad5 fiber domains with those of Ad serotype 3, which binds to a receptor distinct from CAR, and targeted virus replication. Fiber chimerism resulted in efficient cytopathicity to primary melanoma cells, which was at least 10(4)-fold increased relative to Ad5wt. Since viral infectivity mediated by such modified viral capsids was not cell type-specific, it was pivotal to carefully restrict adenoviral replication to target cells. Towards this end, we replaced both E1A and E4 promoters of fiber chimeric viruses by tyrosinase enhancer/promoter constructs. The resulting viruses showed melanoma-specific expression of E1A and E4 and combined efficient virus replication and cell killing in melanoma cell lines and primary melanoma cells with a remarkable specificity profile that implements strong attenuation in nonmelanoma cells, including normal fibroblasts and keratinocytes.     

Experience in long-term clofelin use in the treatment of glaucoma

A long (4-14 years, the mean period 7.8 +/- 1.5) follow-up of 52 patients with primary open-angle glaucoma, regularly administered clofelin instillations (over the entire follow-up) has demonstrated a manifest hypotensive and a good functional result of such therapy. Despite reduction of systemic arterial pressure induced by clofelin instillations, rheo-ophthalmography has shown enhanced blood stream in ocular vessels. 52 percent of patients were administered no miotics but only clofelin (16 patients, 28 eyes) or clofelin+timolol (11 patients, 17 eyes).     

Synthesis and biological activity of 3-N-substitued 2,5-dichloro-4,4-dimethoxy-5-allylcyclopent-2-ene-1-ones

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 26, No. 4, pp. 55–57, April, 1992.