ABSTRACT
The precise molecular events involved in the development of drug resistance (DR) remain largely unknown. Raf is an intermediate in the signal transduction cascades initiated by growth factors. The hypothesis behind the following studies is that deregulated Raf-1 expression plays a role in the development of drug resistance. A positive correlation was observed between increased Raf-1 activity and increased values for IC50 for doxorubicin in established cell lines. The National Cancer Institute/Adriamycin Resistant (NCI/ADR-RES) cell line exhibited both the highest Raf-1 activity and the highest IC50 values for doxorubicin (Adriamycin). In contrast, the MCF-7 cell line exhibited both lower Raf activity and lower IC50 values for doxorubicin. While MCF-7 cells transfected with either constitutively active DeltaRaf-1 or conditionally active DeltaRaf-1:AR demonstrated increased IC50 values for doxorubicin and a reduced capacity to undergo apoptosis after doxorubicin treatment as compared with parental cell lines. Moreover, growth curves performed show that both the constitutively and conditionally active forms of Raf-1 do not increase growth as compared with the parental MCF-7 cell line. This is important because it implies that higher cell counts between Raf transfectants and the parental MCF-7 cell line are attributable to differences in DR, not growth rates. These observations suggest a role for the Raf-1 protooncogene in the regulation of DR.
Subject(s)
Antineoplastic Agents/pharmacology , Doxorubicin/pharmacology , Proto-Oncogene Proteins c-raf/physiology , Signal Transduction , Annexin A5/metabolism , Apoptosis/drug effects , Cell Division/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Flow Cytometry , Gene Expression , Green Fluorescent Proteins , Humans , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Microscopy, Confocal , Plasmids/genetics , Protein Binding , Proto-Oncogene Proteins c-raf/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Testosterone/pharmacology , Tumor Cells, Cultured/drug effectsABSTRACT
PURPOSE: This paper describes a clinic- and community-based diabetes intervention program designed to improve dietary, physical activity, and self-care behaviors of older African American women with type 2 diabetes. It also describes the study to evaluate this program and baseline characteristics of participants. METHODS: The New Leaf ... Choices for Healthy Living With Diabetes program consists of 4 clinic-based health counselor visits, a community intervention with 12 monthly phone calls from peer counselors, and 3 group sessions. A randomized, controlled trial to evaluate the effectiveness of this intervention is described. RESULTS: Seventeen focus groups of African American women were used to assessed the cultural relevance/acceptability of the intervention and measurement instruments. For the randomized trial, 200 African American women with type 2 diabetes were recruited from 7 practices in central North Carolina. Mean age was 59, mean diabetes duration was 10 years, and participants were markedly overweight and physically inactive. CONCLUSIONS: Participants found this program to be culturally relevant and acceptable. Its effects on diet, physical activity, and self-care behaviors will be assessed in a randomized trial.
