Clin Cancer Res
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A single high-dose cycle of chemotherapy with stem cell support can produce disease-free survival of 15-20% for at least 3 years in women with responding stage IV breast cancer. North American Autologous Bone Marrow Transplant Registry data suggest that a complete response (CR) is the single most important prognostic factor associated with prolonged disease-free survival. Therefore, if sequential high-dose chemotherapy can increase the CR rate, then perhaps an increased proportion of patients will remain disease free. ⋯ Seventy-eight percent are progression-free at a median follow-up of 14 months (range, 3-24+). Three sequential cycles of high-dose chemotherapy are feasible and were administered in this study with no mortality. Single agent paclitaxel at doses up to 825 mg/m2 were well tolerated with moderate reversible toxicity.
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The excessive proliferation of the myeloid marrow compartment in Philadelphia chromosome (Ph)-positive acute and chronic leukemias has been largely attributed to a hyperactive and autonomously acting hybrid tyrosine kinase BCR-ABL, a product of the fusion between the second exon of the c-ABL proto-oncogene and 5' portions of the BCR gene on chromosome 22. This specific molecular event, amenable to attack with specifically designed inhibitors, has recently been successfully influenced by the drug CGP-57148 in mammalian cells transfected with full-length BCR-ABL gene and expressing full-length p210Bcr-Abl protein, as well as in primary human leukemic cells expressing p210Bcr-Abl fusion protein. In view of the heterogeneity of BCR-ABL transcripts associated with various phenotypes, we investigated the effect of CGP-57148 on p190Bcr-Abl- and p210Bcr-Abl-expressing, patient-derived cell lines and primary intact blast cells. ⋯ Exposure time and dose appeared to be important variables among various cell types. Moreover, effective doses appeared uniformly harmless to cells lacking BCR-ABL protein functioning as tyrosine kinase. Thus, the continuous exposure of target cells, at least during the initial period of 24-48 h, may prove to be an important variable in the design of in vitro and in vivo therapy using tyrosine kinase inhibitors.