Biodistribution of Alpha-Fetoprotein-Containing Noncovalent Complex Aimpila with Antitumor Activity.

Biodistribution of [125I]Aimpila (20 mg/kg) in the tumor and normal tissues, including the mammary gland tissue, after single oral dose was studied in BALB/c nude mice with T47D/ReCAF+++ human breast tumor sensitive to this drug and in closely related BALB/c nude+mice without tumors. The maximum concentration of [125I]Aimpila was in fact the same in the tumor and in the mammary gland, while the time course of its accumulation/elimination differed. The time of the maximum accumulation of the drug in the tumor was shorter and its persistence longer than in normal tissue. After 24 h, label concentration in the tumor was 4.5 times higher (p=0.002). Differences in the time course of label accumulation in the tumor were detected. The maximum ratio of tumor/blood concentrations of the preparation was recorded in 1 h after administration. [125I]Aimpila and [125I]alpha-fetoprotein accumulated in the tumor in comparable concentrations and were eliminated simultaneously at the same rate. The results of comparative analysis of accumulation of the labeled compounds in Aimpila-sensitive T47D/RECAF+++ tumor from 0.5 to 9.0 h after drug administration could be interpreted as a result of possible receptor-mediated binding of the complex with the tumor at the expense of the alpha-fetoprotein transporting part. Differences in the parameters of [125I]Aimpila biodistribution in the tumor and normal mammary tissue indirectly attested to selective antiproliferative activity of the complex.

Effect of mesna on lethal effect and hematological toxicity of taxol and vepeside in mice.

Mesna, an SH-containing uroprotector, attenuates the lethal effect and hematological toxicity of vepeside and taxol, but did not reduce specific activities of the studied cytostatics in mice with transplanted tumors. This selective antitoxic effect of mesna towards vepeside and taxol allows to intensify the anticancer chemotherapy with these highly effective but extremely toxic cytostatics and to improve the efficiency of anticancer therapy.

[A new method for the intravital assessment of the functional activity of the membrane transporters performing the efflux of antitumor preparations from the cells of solid tumor specimens]. / Novyi metod prizhiznennoi otsenki funktsional'noi aktivnosti membrannykh transporterov, osushchestvliaiushchikh vybros protivoopukholevykh preparatov iz kletok, v obraztsakh solidnykh opukholei.

A new method for intravital assessment of the functional activity of anticancer drug efflux transporters in intact solid tumor specimens was developed. The method is based on the well-known approach to the transporter functional evaluation by intracellular accumulation of antitumor drugs and particularly the anthracycline antibiotic doxorubicin (Dox). The main new point of the method providing investigation of intact solid tumor specimens which markedly simplified the procedure is the fact that the intratissue and intracellular accumulation of Dox is determined not by the level of the drug in the tissue but by its fluorescence decrease in the incubation medium. To assess just the intracellular content of Dox and to estimate the transporter functional activity, investigation of the influence of membrane transporter inhibitors such as verapamil (P-gp inhibitor) and sodium azide (inhibitor of all the energy-dependent ABC transporters) on the drug fluorescence decrease in the incubation medium is stipulated. The validity of such an approach was experimentally proved with the specimens of the Ehrlich solid tumor transplants in mice (a sensitive variant of the tumor and the tumor with induced drug resistance). Biopsy specimens of human breast tumors were investigated with the new method and functional activity of various efflux transporters was revealed: (1) only P-gp, (2) both P-gp and other ABC transporters, (3) only transporters different from P-gp, (4) no functional activity of efflux transporters. The main trends of the further investigation of efflux transporter functional activity in human solid tumors possible for the first time with the use of the new method are defined.

[Effect of calcium gluconate on the toxicity and antitumor of doxorubicin in mice]. / Vliianie gliukonata kaltsiia na toksichnost' i protivoopukholevuiu aktivnost' doksorubitsina u myshei.

The effect of calcium gluconate on the toxicity and specific activity of the anthracycline antibiotic doxorubicin was studied on mice with transplanted hemoblastosis La or plasmocytoma MOPS-406. In both cases after the animal exposure to nontoxic therapeutic doses of doxorubicin no influence of calcium gluconate on the antibiotic antitumor activity was observed. When doxorubicin was used in toxic (and even lethal) doses the antitoxic effect of calcium gluconate and an increase of the antibiotic therapeutic activity were stated. The combination of calcium gluconate and doxorubicin made it possible to significantly increase the maximum therapeutic effect of doxorubicin (higher levels of the animal survival and some cures) and to widen the ranges of the drug therapeutic doses at the account of decreasing the toxicity of the antibiotic and increasing its dose. The results suggested that the antitoxic modifier calcium gluconate could be used for increasing anticancer efficacy of doxorubicin which is given now at the total dose limit of 550 mg/m2 even in cases with preserved tumor sensitivity to the drug.

[Effect of MESNA on intracellular accumulation of doxorubicin and its interaction with DNA]. / Issledovanie vliianiia MESNA na vnutrikletochnoe nakoplenie i vzaimodeistvie doksorubitsina s DNK.

The effect of MESNA, an uroprotector (sodium 2-mercaptoethane sulfonate) on intracellular accumulation of doxorubicin and its interaction with DNA was studied in the cultures of the cells of human ovary carcinoma (CaOV) and normal epithelial kidney cells of green monkeys (VERO). The study was performed with methods developed by the authors. The results showed that MESNA had no effect on the qualitative and quantitative characteristics of the indicated processes in both the types of the doxorubicin sensitive cells. It was concluded that with the combined use of doxorubicin and phosphamide or cyclophosphane the use of MESNA for lowering the urotoxic action of oxazophosphorines had no effect on the biological efficacy of doxorubicin. The necessity of studying the possible modifying effect of MESNA in the cultures of doxorubicin resistant cells and in vivo is indicated.

[The induction of tolerance in mice for a human melanoma graft]. / Induktsiia tolerantnosti u myshei k transplantatu melanomy cheloveka.

Mouse skin allografts and intramuscular BRO human melanoma xenografts were successfully established in phenotypically normal mice after inducing immunological tolerance in the recipients. Tolerance was achieved by inoculating allogenic embryonic liver cells after the whole-body irradiation. No immunological rejection was evident in BRO xenografts for 34 days after transplantation. During this period the BRO cells invaded neighboring tissues and formed distant micrometastases in the lungs.