Developing Treatments for Cancer

            The system of cancer treatment has long been targeted at DNA synthesis and cell division, neglecting other, more concentrated approaches on distinct cancers. The discovery of the Gleevec drug revealed an unprecedented anticancer system targeting only leukemic cells, sparring healthy cells and as a result, led to a new therapeutic approach on the growth inhibition of tumor cell lines. Gleevec was originally derived from a lead compound detected in a screening for inhibitors of protein kinase C (Capdeville et al.: 2002). The identified lead compound was observed to have a high potential for diversity and thus susceptible to chemical change to produce a compound greater in its effectiveness and selectivity for desired targets. The chemical optimization of the compound ultimately led to the imatinib compound (Gleevec) classified as a small molecule tyrosine kinase inhibitor. .
             Gleevec was first demonstrated to exhibit its specific inhibitory effects on the elevated TK activity of the BCR-ABL protein by disrupting ATP and substrate binding of the TK catalytic domain, thereby halting proliferation of immature myelocytes in case of chronic myelogenous leukemia (CML). Moreover, Gleevec is shown to specifically target and inhibit certain known TKs, such as ABL, c-KIT and PDGF receptor (PDGFR), which are all prominent in hematologic and cytogenetic pathogenesis. As in the case of most anticancer therapeutic drugs, cancer cells that are resistant to these specific drugs are evolved by random somatic mutations during the proliferation phase. Although Gleevec showed remarkable responses in CML during early stages of the disease, the later advanced stages result in point mutations identified in a list of BCR-ABL and other TKs, render imatinib-drug resistance and adverse disease progression. The TK mutants with drug resisting capabilities are able to undergo constitutive activation of signaling pathways, promote an increased efflux of the drug, and even generate plasma proteins that bind to the drug to decrease its concentration (Krause et al: 2005).