The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph+) leukemia has prompted the development of second-generation compounds ...active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph+ patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317.
The influence of individual stages of the rat estrous cycle during exposure to I-nitroso-I-methylurea (NMU) on mammary tumor incidence, latency, number, and cytosol receptor dynamics for estrogen and ...progesterone was determined. Virgin female Buffalo rats were separated into three groups on Day 53 according to their vaginal smear pattern. NMU (5 mg/100 g body weight, i.v.) was administered in three monthly doses beginning at 53 to 55 days of age on diestrus, proestrus, or estrus between 9:00 and 11:00 a.m. Groups of rats had their second and third injections of NMU on the same day of the estrous cycle as their initial injection. All animals were killed during the morning on a diestrus day. Receptors for estrogen and progesterone were determined by a modified dextran-coated charcoal method and by sucrose density gradient analysis. Mean latencies to first tumor appearance in diestrus, proestrus, and estrus groups were 104.4, 83.6, and 91.4 days, respectively (p less than 0.05, diestrus versus estrus and proestrus) following the first NMU injection. The mean number of tumors per rat was significantly higher in rats injected on proestrus (4.5) or estrus (4.3) than on diestrus (2.0). Estradiol bound to receptor sedimented at 8 and 4 s and was suppressed by diethylstilbestrol and estradiol. Progesterone receptor migrated to 7.8 and 4 s regions. Estrogen receptor incidence (100%) and content (16.7 fmol/mg cytosol protein) was highest in rats injected on diestrus. In the proestrus and estrus injected groups, estrogen receptor incidence was 95 and 63% and content was 10.2 and 11.2 fmol/mg protein, respectively. The affinity of estradiol for its receptor was not significantly altered in any group. Although there were no statistically significant difference in progesterone receptor incidence or affinity between groups, progesterone receptor content (74.6 fmol/mg cytosol protein) was significantly higher in tumors from rats injected on proestrus than on diestrus. These data suggest that the prevailing hormonal milieu of the estrous cycle during NMU exposure may be critically important to the subsequent biological behavior and steroid receptor status of carcinogen-induced rat mammary tumors.
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