Hsp70 chaperone-based gel composition as a novel immunotherapeutic anti-tumor tool

The recent advances in designing Hsp70-based anti-cancer vaccines and the ability of the chaperone to penetrate inside a living cell prompted us to develop a non-invasive method for the treatment of surface tumors. We designed hydrogel-containing gel-forming substances and human recombinant Hsp70 and applied them on the surface of a 7-day-old B16F10 melanoma tumor. According to the results of histochemistry, Hsp70 diffused through skin layer inside the B16 tumor, and this transport was proved by biochemical data. The application of Hsp70 gel reduced the rate of tumor growth by 64 % and prolonged the life of animals by 46 %. Increased survival was correlated with the enhancement of B16-specific cytotoxicity and up-regulation of gamma–interferon production. Taken together, the data confirm the anti-tumor effect of pure recombinant Hsp70 delivered intratumorally and demonstrate the relevance of a novel non-invasive technology of Hsp70-based therapy.     

Manifestation of synergism under simultaneous action of hyperthermia and antitumor drugs on yeast cells

For the purpose of obtaining novel fundamental knowledge, there are studied regularities of manifestation of synergism under simultaneous combined action of hyperthermia (47.5–60°C) and antitumor compounds (cyclophosphamide, cisplatin) on survival of yeast cells. To calculate the efficiency of synergic interaction, we used experimentally obtained dependences of cell survival on the duration of action after separate and simultaneous action of chemical agent and hyperthermia. A certain diapason of temperatures is shown, within which a synergic increase of the action of antitumor drug and hyperthermia occurs. Any deviation of temperature from the optimal value leads to a decrease of synergism. A possible mechanism of the revealed regularity is discussed.     

The Worst Drug Rule Revisited: Mathematical Modeling of Cyclic Cancer Treatments

In drug treatments of cancer, cyclic treatment strategies are characterized by alternating applications of two (or more) different drugs, given one at a time. One of the main problems of drug treatment in cancer is associated with the generation of drug resistance by mutations of cancerous cells. We use mathematical methods to develop general guidelines on optimal cyclic treatment scheduling, with the aim of minimizing the resistance generation. We define a condition on the drugs’ potencies which allows for a relatively successful application of cyclic therapies. We find that the best strategy is to start with the stronger drug, but use longer cycle durations for the weaker drug. We further investigate the situation where a degree of cross-resistance is present, such that certain mutations cause cells to become resistant to both drugs simultaneously. We show that the general rule (best-drug-first, worst-drug-longer) is unchanged by the presence of cross-resistance. We design a systematic method to test all strategies and come up with the optimal timing and drug order. The role of various constraints in the optimal therapy design, and in particular, suboptimal treatment durations and drug toxicity, is considered. The connection with the “worst drug rule” of Day (Cancer Res. 46:3876, 1986b) is discussed.