Cancer Therapy on Target

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Science  20 Apr 2001:
Vol. 292, Issue 5516, pp. 399-401
DOI: 10.1126/science.292.5516.399e

A major limitation of conventional cancer drugs is that they kill rapidly growing normal cells as well as cancer cells. Since the discovery that cancer cells contain specific molecular genetic alterations, researchers have labored to develop new therapies that target these alterations selectively, with the hope that such therapies would kill cancer cells primarily. In the case of chronic myeloid leukemia (CML), there is a chromosomal translocation (yielding the Philadelphia chromosome) that fuses two unrelated genes, BCR and ABL. This translocation creates a BCR-ABL fusion protein with a constitutive tyrosine kinase activity that has been shown to be causally involved in the disease. A small-molecule inhibitor of BCR-ABL, called STI571 (for the crystal structure of the ABL-STI571 complex, see Schindler et al., Reports, 15 Sept 2000, p. 1938) was designed in the early 1990s; it was brought to phase I clinical trials as an anticancer agent on the basis of promising results in cell culture studies and animal models.

Druker et al. report the exciting and highly anticipated results of these clinical trials. When administered orally at a dose of 300 milligrams per day or higher, STI571 produced complete hematologic responses in 53 of 54 patients with early-stage CML (chronic phase) without serious side effects. In a second study, Druker et al. observed hematologic responses in 55 to 70% of patients with a more advanced stage of CML (blast crisis) or with acute lymphoblastic leukemia (ALL), although the responses were less durable than those seen in patients with chronic phase CML. Furthermore, cell culture studies had shown that STI571 inhibits the c-Kit tyrosine kinase, leading Joensuu et al. to test the efficacy of the drug in one patient with a gastrointestinal stromal tumor, a tumor type known to express the c-Kit kinase and for which there is no effective therapy. This patient also exhibited a strong response to the drug, showing a 52% decrease in tumor volume within 1 month. These findings offer great hope for the future success of targeted therapies for cancer. — PAK

N. Engl. J. Med. 344, 1031; 1038; 1052 (2001).

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