Effects of the guanine-quadruplex telomerase inhibitor BRACO-19 on tumour cells: Evidence of selective action on telomere maintenance

1504 STA-4783 is a newly synthesized bis-thiobenzoylhydrazide compound (MW: 400) that promotes tumor-specific induction of heat shock protein 70 (HSP70) and exhibits significant enhancement of Paclitaxel efficacy in a variety of human tumor xenografts in nude mice and mouse syngeneic tumor models. Although STA-4783 exhibited little to no anti-tumor activity when administered as a single agent in these models, it dramatically increased the efficacy of both low sub-optimal doses of Paclitaxel as well as the higher maximum-tolerated doses of Paclitaxel. Both a reduction in tumor size and an increase in survival were observed. STA-4783 induced strong HSP70 expression in many tumor cell lines including human breast carcinoma MDA-435 (at 0.1 μM), but not in normal cell lines such as human mammary epithelial cells HMEC or human renal epithelial cells HREC (at 5 μM) in vitro. The substantially improved anti-tumor activity of the combination therapy was seen in mouse xenograft models with human tumors of various origins, including breast (MDA-435, MCF-7, ZR-75-1), lung (RERF), and lymphoma (U937). This enhancement in efficacy was dose-dependent with regard to STA-4783. STA-4783 co-treatment did not result in additional toxicity above that observed with Paclitaxel alone. In the detailed GLP toxicity and DMPK studies in rats and dogs, no increased toxicity was observed. STA-4783 had no influence on the pharmacokinetics of Paclitaxel. The Paclitaxel enhancement of STA-4783 was not observed in vitro and was absent in SCID-beige models in vivo, suggesting an immune-mediated mechanism. The HSP70 induction by STA-4783 in tumor cells may activate the immune system, thereby adding to the anti-tumor activity of Paclitaxel. In fact, it has been observed that treatment of tumor cells with STA-4783 and related compounds that induce HSP70, but not compounds that fail to induce HSP70, increased the lysis of tumor cells by mouse splenocytes. A phase I trial is underway to define the maximum tolerated dose, toxicity, and pharmacokinetics of STA-4783 combined with Paclitaxel.