Novel indolocarbazole derivative 12-(alpha-L-arabinopyranosyl)indolo[2,3-alpha]pyrrolo[3,4-c]carbazole-5,7-dione (AIC) demonstrated high potency (at submicromolar concentrations) against the NCI panel of human tumor cell lines and transplanted tumors in vivo. In search of tentative targets for AIC, we found that the drug formed high affinity intercalative complexes with d(AT)(20), d(GC)(20) and calf thymus DNA (binding constants (1.6x10(6)) M(-1)< or =K(a)< or =(3.3x10(6)) M(-1)). The drug intercalated preferentially into GC pairs of the duplex. Importantly, the concentrations at which AIC formed the intercalative complexes with DNA (C< or =1 microM) were identical to the concentrations that triggered p53-dependent gene reporter transactivation, the replication block, the inhibition of topoisomerase I-mediated DNA relaxation and death of HCT116 human colon carcinoma cells. We conclude that the formation of high affinity intercalative complexes with DNA is an important factor for anticancer efficacy of AIC.

The photodynamic activity and pharmacokinetics of a new liposomal form (LF) of the sensitizer Photosense based on aluminum sulfophthalocyanine salts have been studied in comparison to those of the standard form (SF) representing a 0.2% aqueous solution of the parent substance. The effective therapeutic doze of the LF of Photosense in mice bearing Ehrlich's tumor was 1 mg/kg, which is four times as small as the effective dose of the SF. The selectivity of accumulation in the tumor tissue 24 h after administration for the LF of Photosense was 1.5 times higher than for the SF. The drug accumulation in skin (determined by the fluorescence intensity) on the 7th days of experiment for the LF of Photosense was 1.6 times lower than for the SF. The pharmacokinetics of the LF of Photosense in mice without tumors significantly differs from the behavior of the SF.In recent years, the photodynamic therapy (PDT) and fluorescent diagnostics (FLD) of neoplasms have been extensively developed both in the experimental oncology and on the clinical level. In Russia, several potential photosensitizers for PDT and FLD are currently under clinical investigation [1 -4]. Among these, most thoroughly studied is Photosense -a domestic photosensitizer of the second generation -representing a mixture of sodium salts of sulfonated aluminum phthalocyanine, which is synthesized using an original patented technology developed at the State Research Institute of Organic Semiproducts and Dyes (Moscow) [5,6].Previous investigations into the mechanisms of the photodynamic damage of inoculated tumors by Photosense showed that the therapeutic activity of this drug is a multifactor process including (i) necrosis and apoptosis of tumor cells under the direct action of cytotoxic agents (singlet oxygen, free radicals) generated in the course of PDT and (ii) ischemic necrosis caused by the violated blood flow in vessels of the tumor [7]. The results of pathomorphological investigations [7] showed that the direct photodynamic effect of Photosense on the cells and tissues of parenchyma was more pronounced when the period of time between the photosensitizer administration and irradiation exceeds 24 h. The active components of Photosense have various degrees of sulfonation and, hence, differently penetrate through vessel walls and influence the parenchyma [8,9]. The amphiphilic character of the photosensitizer also significantly influences the ability of Photosense to penetrate through the membranes of tumor cells. The attachment of two biotin residues to the molecule of Photosense provided for nearly optimum amphiphilic properties and significantly increased the efficacy of the drug action [10].

The efficiency of photodynamic therapy with photosensitizer Tiosens (Russia) was evaluated in mono- and combined therapy of rats with malignant gliomas (glioblastoma 101/8, oligodendroglioma 14-4-9, and C6 glioma). The efficiency of photodynamic monotherapy was not high: the animals died from brain edema developing in tumor tissue and in the adjacent normal cerebral tissue. Pathomorphological studies of tumor tissue detected necrosis and apoptosis, destruction of vessels with hemorrhages, and vascular thrombosis. Combined therapy for malignant gliomas including Tiosens photodynamic therapy and subsequent temodal or lysomustine chemotherapy, was the most effective. In glioblastoma 101/8, combined therapy with lysomustine or temodal led to prolongation of the lifespan by 127 %; 62.5 and 50 % rats were cured, respectively; in oligodendroglioma 14-4-9, animal lifespan was prolonged by 80 and 60 %, with 43 and 45 % rats cured, respectively. Glioma C6 was least sensitive to therapy.

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