Effect of CH-35, a novel anti-tumor colchicine analogue, on breast cancer cells overexpressing the ßIII isotype of tubulin.

The subunit protein of microtubules is tubulin, which has been the target for some of the most successful and widely used anti-tumor drugs. Most of the drugs that target tubulin bind to the ß subunit. There are many isotypes of ß-tubulin and their distributions differ among different tissues. The ßIII isotype is over-expressed in many tumors, particularly those that are aggressive, metastatic, and drug resistant. We have previously reported the design and synthesis of a series of compounds to fit the colchicine site on ßIII but not on the other isotypes. In the current study, we tested the toxicity and the anti-tumor activity of one of these compounds, CH-35, on the human breast tumor MDA-MB-231 over-expressing ßIII in a xenogeneic mouse model. We found that CH-35 was as toxic as Taxol® in vivo. Although the ßIII-over-expressing cells developed into very fast-growing tumors, CH-35 was more effective against this tumor than was Taxol. Our results suggest that CH-35 is a promising candidate for future drug development.

Computational design and biological testing of highly cytotoxic colchicine ring A modifications.

Microtubules are the primary target for many anti-cancer drugs, the majority of which bind specifically to beta-tubulin. The existence of several beta-tubulin isotypes, coupled with their varied expression in normal and cancerous cells provides a platform upon which to construct selective chemotherapeutic agents. We have examined five prevalent human beta-tubulin isotypes and identified the colchicine-binding site as the most promising for drug design based on specificity. Using this binding site as a template, we have designed several colchicine derivatives and computationally probed them for affinity to the beta-tubulin isotypes. These compounds were synthesized and subjected to cytotoxicity assays to determine their effectiveness against several cancerous cell lines. We observed a correlation between computational-binding predictions and experimentally determined IC(50) values, demonstrating the utility of computational screening in the design of more effective colchicine derivatives. The most promising derivative exhibited an IC(50) approximately threefold lower than values previously reported for either colchicine or paclitaxel, demonstrating the utility of computational design and assessment of binding to tubulin.

New malaria chemotherapy developed by utilization of a unique parasite transport system.

During its development in the host red cell, the human malarial parasite causes profound alteration in the permeability of the host cell membrane. These membrane transport systems(s) play a role in the development of the intra-erythrocytic parasite in its need to take up solutes and nutrients from the extracellular medium and the disposal of metabolic wastes. Importantly, the properties of these parasite induced transport systems are significantly different from those in normal human cells. Hence, such systems are of considerable interest for their potential use in anti-malarial chemotherapy, both by (i). inhibiting the transport and hence depriving the parasite of nutrients essential for its development, or (ii). by designing cytotoxic drugs which selectively enter the parasite through these induced transporter routes and hence cannot enter normal mammalian cells. Since our discovery that optical isomers of nucleosides (such as L- adenosine or L- thymidine) were selectively transported into malaria infected cells through the induced transporter, L-nucleoside drug "carriers" were actively synthesized as potentially new therapeutic agents. The compounds are dinucleoside phosphate dimers, where each "carrier" (a L-nucleoside) has been conjugated to known anti-malarial agents, such as 5'-fluro-uridine through the 3' and 5'-OH and a phosphate group. A very large series of these drugs have been synthesized with varying conjugations. The dimers are extremely toxic against malaria and experimental evidence has confirmed that they are incapable of entering normal mammalian cells. This review discusses their mechanism of action and potential as new anti-malarial chemotherapy as well as the role played by the membrane transport system of malaria infected cells as a target for malaria chemotherapy.