Lorus Therapeutics Inc
GTI-2040

ANTISENSE
The human metabolism is essentially controlled by proteins produced by the body. Since most human diseases, including cancer, can be traced to faulty protein production, traditional therapeutics are designed to interact with the disease causing proteins. Antisense therapeutics take a different approach to treatment; they are designed to prevent the production of the proteins causing the disease.

In cancer, gene mutations interfere with normal protein synthesis, resulting in uncontrolled cell growth. The genes controlling cell growth are comprised of a series of complementary base sequences within the two strands of DNA. In order for the instructions in the DNA to be carried-out, the genetic code held in the DNA base sequences is transcribed as messenger RNA (mRNA), which is then “translated” and used by the cell for protein synthesis. Antisense drugs work by blocking the translation process, thereby inhibiting the expression of the gene, and preventing inappropriate protein synthesis.

In acting at this earlier stage in the disease-causing process, antisense drugs have the potential to provide greater therapeutic benefit than traditional drugs, which do not act until the disease-causing protein has already been produced. In addition, antisense treatment may be more selective, and as a result, more effective and less toxic than traditional therapies.

Naturally, the effectiveness of an antisense drug is largely dependent on the protein targeted. When examining antisense targets, Lorus chose ribonucleotide reductase (RNR) because of its significance in the uncontrolled cell growth associated with essentially every cancer. RNR is a highly regulated cell enzyme that is essential for DNA synthesis and repair. RNR catalyzes the formation of deoxyribonucleotides, which are required for building the cell's DNA and thus responsible for DNA replication and cell division. Lorus' antisense therapeutics are designed to inhibit this process.

GTI-2040
GTI-2040 is an antisense, antitumor agent that targets the R2 component of RNR. Since it has been noted that levels of R2 are elevated in cancer cells, an antisense molecule that binds to the mRNA coding for R2 inhibits the replication of diseased cells. Furthermore, research indicates that reducing the levels of R2 that are expressed in cells leads to lowered resistance levels to other pharmaceutical compounds that might be used in combination therapy with GTI-2040.

In studies during treatment with GTI-2040, when levels of RNR were reduced, marked inhibition of human tumor growth was observed. The responses to treatment with GTI-2040 included significant tumor growth reduction, disease stabilization (i.e., very little or no tumor growth), and tumor regressions. GTI-2040 is currently in a Phase II clinical trial for the treatment of renal cell carcinoma, the most common form of kidney cancer. GTI-2040 is being studied in combination with capecitabine, an oral chemotherapeutic agent that has shown potential against renal cell carcinoma. In addition, Lorus is collaborating with the United States National Cancer Institute in a multiple Phase II clinical program to examine the impact of GTI-2040 in a variety of other cancer types.

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