Research

Since cancer cells proliferate faster than normal cells, DNA replication is therefore significantly greater in cancer cells. Many chemotherapeutic agents used in cancer treatments hinder cancer cell replication by inducing DNA breaks.

Cells repair DNA by a variety of mechanisms, and cancer cells do it even more than normal cells, which results in a lessening of the efficiency of cancer therapies. This loss in efficiency necessitates the use of high concentrations of chemotherapeutics in order to obtain a satisfactory inhibition of cancer proliferation.

These substances are, however, very toxic and have damaging side effects, which is why hindering tumor cell proliferation is an essential non-optimized oncology need.

DNA double-strand can break in many ways: it may happen in the middle, or at both ends of one strand, or on both strands. Specific enzymes are responsible for repairing each of such breaks so the cell can continue to replicate.

Double-strand breaks are more frequent in cancer cells than in normal cells, since this type of breaks happen more often during their replication. Oncozyme has demonstrated that the endo-exonuclease enzyme is involved in repairing DNA double-strand breaks.

This enzyme plays an essential role in cancer cell replication, which means inhibiting endo-exonuclease is a promising scientific option to hinder tumor cell proliferation.

Oncozyme selected a series of potential inhibitors of endo-exonuclease and tested the potential use of these inhibitors to treat cancer in vitro and in vivo. Pentamidine was identified as the most promising inhibitor, having high synergistic potential with many chemotherapeutic agents that target DNA.

In the Lewis lung carcinoma preclinical model, pentamidine was as effective an anti-cancer agent as cis-platinum. There is a great opportunity to use both agents in combination.

Similar results were obtained in a human xenograft experiment on colon cancer, where pentamidine used alone was as effective as 5-fluorouracil (5-FU). Again, the two compounds could be used in combination creating a powerful synergistic effect.

Based on these encouraging preclinical results, Oncozyme developed a clinical program targeting cancer to evaluate its pentamidine bis (2-hydroxyethanesulfonate) IV solution, OCZ103-OS.

Oncozyme completed two phase I/II studies, one in colon cancer patients and another one in pancreatic cancer patients. Results of these studies were so promising that the company initiated a phase II study in colon cancer patients and a phase IIa study in lung cancer patients. Both studies are currently in progress.

Sadekova S, Chow TY. Over-expression of the NUD1-coded endo-exonuclease in Saccharomyces cerevisiae enhances DNA recombination and repair. Curr Genet 1996;30:50-55.

Semionov A, Cournoyer D, Chow TY. Transient expression of Saccharomyces cerevisiae endo-exonuclease NUD1 gene increases the frequency of extrachromosomal homologous recombination in mouse Ltk- fibroblasts. Mutat Res 1999;435:129-139

Terry Y-K Chow, Moulay A. Alaoui-Jamali, Chiaoli Yeh, Leonard Yuen, and David Griller. The DNA Double-Stranded Break Repair Protein Endo-Exonuclease As A Therapeutic Target For Cancer. Molec. Cancer Therapeut. 3(8):911-919, 2004.

Sibgat A. Choudhury, Benyam Asefa, Ashley Webb, Dindial Ramotar, and Terry Y-K Chow. Functional and genetic analysis of the Saccharomyces cerevisiae RNC1/TRM2: Evidences for its involvement in DNA double-strand break repair. 2007. Molec. Cell Biochem. 300 :215-216.

Sibgat A. Choudhury, Benyam Asefa, Paul Kauler, and Terry Y-K Chow. Synergistic function of TRM2/RNC1 and EXO1 in DNA double-strand break repair in Saccharomyces cerevisiae. 2007, Molec. Cell Biochem . 304; 127-134.

Choudhury SA., Kauler, P., and Chow, T.Y.-K. Silencing of endo-exonuclease expression sensitizes mouse B16F10 melanoma cells to DNA damaging agents. 2007, Invest. New Drugs 25:399-410.