5 research outputs found
Nationwide Study of Breast Cancer Risk Factors in Latinas
Breast cancer is the most common cancer among American women. Any woman can be affected by breast cancer, with risk for the disease increasing with age. Risk for breast cancer is also exacerbated in women who have certain genetic alterations. Mutations in the BRCA1 and BRCA2 genes predispose women to breast and ovarian cancer, and are increasingly recognized in prostate and pancreatic cancers (1-3). In Caucasian and Asian ethnicities BRCA mutations are associated with basal-type/triple-negative disease. However this association between BRCA gene mutations and basal/triple-negative disease has been understudied in other ethnicities (4-6). The incidence and mortality of breast cancer of Hispanics and Native Americans are lower than other ethnicities; however they are underrepresented in epidemiological and clinical studies. Further, it is known that common recurrent mutations in BRCA1 and BRCA2 genes exist in Hispanic/Latino communities which account for 35-45% of mutation carriers (7, 8). The objective of our study is thus to investigate triple-negative disease and BRCA gene mutations in Hispanic women
Nationwide Study of Breast Cancer Risk Factors in Latinas
Breast cancer is the most common cancer among American women. Any woman can be affected by breast cancer, with risk for the disease increasing with age. Risk for breast cancer is also exacerbated in women who have certain genetic alterations. Mutations in the BRCA1 and BRCA2 genes predispose women to breast and ovarian cancer, and are increasingly recognized in prostate and pancreatic cancers (1-3). In Caucasian and Asian ethnicities BRCA mutations are associated with basal-type/triple-negative disease. However this association between BRCA gene mutations and basal/triple-negative disease has been understudied in other ethnicities (4-6). The incidence and mortality of breast cancer of Hispanics and Native Americans are lower than other ethnicities; however they are underrepresented in epidemiological and clinical studies. Further, it is known that common recurrent mutations in BRCA1 and BRCA2 genes exist in Hispanic/Latino communities which account for 35-45% of mutation carriers (7, 8). The objective of our study is thus to investigate triple negative disease and BRCA gene mutations in Hispanic women
Pharmacophore Modeling of Nilotinib as an Inhibitor of ATP-Binding Cassette Drug Transporters and BCR-ABL Kinase Using a Three-Dimensional Quantitative Structure–Activity Relationship Approach
Nilotinib (Tasigna) is a tyrosine
kinase inhibitor approved by
the FDA to treat chronic phase chronic myeloid leukemia patients.
It is also a transport substrate of the ATP-binding cassette (ABC)
drug efflux transporters ABCB1 (P-glycoprotein, P-gp) and ABCG2 (BCRP),
which may have an effect on the pharmacokinetics and toxicity of this
drug. The goal of this study was to identify pharmacophoric features
of nilotinib in order to potentially develop specific inhibitors of
BCR-ABL kinase with minimal interactions with ABC drug transporters.
Three-dimensional pharmacophore modeling and quantitative structure–activity
relationship (QSAR) studies were carried out on a series of nilotinib
analogues to identify chemical features that contribute to inhibitory
activity of nilotinib against BCR-ABL kinase activity, P-gp, and ABCG2.
Twenty-five derivatives of nilotinib were synthesized and were then
tested to measure their activity to inhibit BCR-ABL kinase and to
inhibit the function of ABC drug transporters. A set of <i>in
vitro</i> experiments including kinase activity and cell-based
transport assays and photolabeling of P-gp and ABCG2 with a transport
substrate, [<sup>125</sup>I]-iodoarylazido-prazosin (IAAP), were carried
out in isolated membranes to evaluate the potency of the derivatives
to inhibit the function of ABC drug transporters and BCR-ABL kinase.
Sixteen, fourteen, and ten compounds were selected as QSAR data sets,
respectively, to generate PHASE v3.1 pharmacophore models for BCR-ABL
kinase, ABCG2, and P-gp inhibitors. The IC<sub>50</sub> values of
these derivatives against P-gp, ABCG2, or BCR-ABL kinase were used
to generate pharmacophore features required for optimal interactions
with these targets. A seven-point pharmacophore (AADDRRR) for BCR-ABL
kinase inhibitory activity, a six-point pharmacophore (ADHRRR) for
ABCG2 inhibitory activity, and a seven-point pharmacophore (AADDRRR)
for P-gp inhibitory activity were generated. The derived models clearly
demonstrate high predictive power for test sets of BCR-ABL, ABCG2,
and P-gp inhibitors. In aggregate, these results should aid in the
development of specific inhibitors of BCR-ABL kinase that exhibit
no or minimal interaction with ABC drug transporters