Interleukin-3 protects Bcr-Abl-transformed hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors.

Bcr-Abl tyrosine kinase has been validated as a molecular target for the treatment of chronic myelogenous leukemia (CML). More recently, it has been reported that CML patients could develop resistance to the Bcr-Abl tyrosine kinase inhibitor, imatinib (STI571, Gleevec), pointing to the need for development of additional Bcr-Abl tyrosine kinase inhibitors or other therapeutic strategies. It was also found that a significant proportion of patients who received the Bcr-Abl inhibitor did not achieve complete cytogenetic response. Mechanisms for incomplete cytogenetic response to Bcr-Abl inhibition are not entirely clear. We report here three new pyrido[2,3-d]pyrimidine Bcr-Abl tyrosine kinase inhibitors, PD164199, PD173952, PD173958, that induced apoptosis of Bcr-Abl-dependent hematopoietic cells. An interleukin-3 (IL-3) autocrine loop was observed previously in primitive CD34(+)/Bcr-Abl(+) leukemic cells in CML patients. Using 32Dp210(Bcr-Abl)and Baf3p210(Bcr-Abl) cells as models, we tested whether IL-3 might protect Bcr-Abltransformed, IL-3-responsive cells from apoptosis caused by Bcr-Abl tyrosine kinase inhibition. Results of trypan blue exclusion, fluoroisothiocyanate-valyl-alanyl-aspartyl-[O-methyl] -fluoromethylketone (FITC-VAD-FMK), and Annexin-V/7-amino-actinomycin D (7-AAD) binding assays indicate that IL-3 could protect Bcr-Abl-transformed, IL-3 responsive hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors. This finding raises the possibility that the IL-3 autocrine loop found in primitive CD34(+)/Bcr-Abl(+) cells in CML patients could contribute to the incomplete eradication of Bcr-Abl(+) cells by Bcr-Abl inhibition.

The impact of intensive case-managed intervention on substance-using pregnant and postpartum women.

This study examines the impact of the Women's Intervention Services and Education (WISE) Project in serving substance-using pregnant and postpartum women through an array of case-managed services and supports. A descriptive analysis of multiple outcome indicators was performed on 152 women who had a minimum 6 months of exposure to WISE services at the time of the analysis. The variables used in the analysis to assess client and program outcomes included substance use, employment, arrests, incarceration, birthweight, and social support. This group of women showed statistically significant improvements across each of these multiple outcome indicators from pre-WISE to WISE discharge. Although the findings of this study are not conclusive because no control group was employed, the results are encouraging and supportive of a growing body of literature that suggests that pregnant and postpartum polydrug-using women can be responsive to case-managed, intensive intervention, with aftercare support.

Case management of pregnant and parenting female crack and polydrug abusers.

The increasing use of crack-cocaine among addicted women and subsequent births of polydrug-exposed infants prompted the State of Florida to undertake initiatives to seek solutions to these problems. This study, focused on one of these initiatives, explored the relationship between service components of a comprehensive treatment program and substance-free time among 120 African American and Caucasian crack-cocaine addicted women. Findings from a multiple regression analysis indicated that aftercare management (p < .0001), vocational services (p < .02), and residential treatment (p < .03) were statistically significant services associated with substance-free time. Although these findings are not conclusive, they are supportive of a growing body of literature that suggests that crack-using and polydrug-using women can be responsive to treatment when it is tailored to their individual needs and includes long-term community support.