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Page 2
When patients developed a resistance to paclitaxel, a search was undertaken for a non-taxane that would have a similar mechanism of action. This was achieved with the discovery of BMS-247550, a semisynthetic analog of the natural product epothilone B. Epithilones are obtained from the fermentation of the cellulose degrading myxobacterium, Sorangium cellulosum. This analog is now in clinical trials.
As I mentioned in my previous article, the glutathione enzyme system serves to disactivate anticancer drugs by forming a less toxic complex. Gamma-glutamylcystine synthetase is a key enzyme in glutathione synthesis. Japanese researchers 5 designed a RNA enzyme (known as a ribozyme) that inhibits the action of the gene responsible for the synthesis of this enzyme. In this manner, the ribozyme reverses the resistance to anticancer drugs. Compounds known as diazenes are also effective in reversing drug resistance. Results indicate that choices need to be made for specific combinations of diazene compound and anticancer drug to be effective in the treatment of certain cancer types. Stimulation of Apoptosis Most anticancer drugs ultimately exert their effects through the stimulation of pathways leading to programmed cell death, or apoptosis. Beta lapachone is very effective in stimulating apoptosis in patients with multiple myeloma. 4Utilizing methods of gene therapy, Ohi and associates 6examined the effectiveness of introducing the apoptosis gene, bcl-Xs, into cancer cells. Although these laboratory studies are promising, it will be some time before this technique will reach the clinic. Agents against hypoxic cells Many tumor cells are hypoxic, or experience a lack of oxygen due to an insufficient supply of blood vessels. As a result, cancer cells in the interior of the tumor tend to be inactive, and do not divide. Although anticancer drugs may kill cells on the exterior portions of the tumor, the hypoxic cells are more likely to survive and develop resistance to anticancer drugs. Tirapazine is the first drug to be developed for its activity towards hypoxic cells.1 Mismatch repair The correct structure and functioning of DNA depends on the exact pairing and binding of its constituent nucleotide bases. If an inaccurate base is inserted in a DNA strand during replication, it is the role of mismatch repair proteins to remove the defective base. The loss of mismatch repair results in multidrug resistance, although the reasons are not clear. Efforts to develop treatments that restore the mismatch repair function are in the early stages. Fibroblast growth factors An additional explanation to account for anticancer drug resistance is provided in a paper by Song and associates. 7They found that elevated levels of fibroblast growth factors found in the extracellular fluid (outside the cells) caused increased resistance to chemotherapeutic drugs, and that an inhibitor of these growth factors (suramin) restored sensitivity to these drugs. These results could provide a basis for designing new treatment strategies.
The copyright of the article Resistance to Anticancer Drugs-2 - Page 2 in Cancer Treatment is owned by . Permission to republish Resistance to Anticancer Drugs-2 - Page 2 in print or online must be granted by the author in writing.
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