作者: Marcela Henao-Tamayo ; Randall J. Basaraba ; Graham R. Stewart ; Mercedes Gonzales-Juarrero ; Douglas B. Young ; Ian M. Orme ; Robert J. Wilkinson ; Diane Ordway ; Ana Paula Junqueira-Kipnis

A mutant of Mycobacterium tuberculosis (Delta 19) lacking the 19-kDa lipoprotein grows well in culture in vitro but was shown here to be essentially incapable of any significant replication in mice, even in mice lacking the gamma interferon gene. Despite this, mice inoculated with Delta 19 were equally protected against an aerosol delivered challenge with M. tuberculosis compared to the conventional BCG vaccine. Cellular responses, including the generation of activated CD4 and CD8 cells secreting gamma interferon, were produced in similar numbers, and lung cells, particularly dendritic macrophages, exhibited high levels of Class-II MHC expression. These data show that despite being highly attenuated, the Delta 19 mutant strongly retained vaccinogenic properties.

Breast cancer research : BCR1区 · 医学

Prolactin receptor antagonism reduces the clonogenic capacity of breast cancer cells and potentiates doxorubicin and paclitaxel cytotoxicity

1区 · 医学

ArticleOA

作者: Howell, Sacha J. ; Anderson, Elizabeth ; Clarke, Robert B. ; Farnie, Gillian ; Hunter, Tom

Abstract:

Introduction:

Exogenous prolactin is mitogenic and antiapoptotic in breast cancer cells, and overexpression of autocrine prolactin cDNA in breast cancer cell lines has been shown to stimulate their growth and to protect against chemotherapy-induced apoptosis. We examined the effects of the 'pure' prolactin receptor antagonist Δ1–9-G129R-hPrl (Δ1–9) on the breast cancer cell number and clonogenicity, alone and in combination with chemotherapy.

Methods:

The effects of doxorubicin, paclitaxel and Δ1–9 on the growth of breast cancer cell lines (MCF-7, T47D, MDA-MB-453, MDA-MB-468 and SK-BR-3) in monolayer culture were assessed by the sulphorhodamine B assay. Effects on clonogenicity were assessed by soft agar assay for the cell lines and by the mammosphere assay for disaggregated primary ductal carcinoma in situ samples. Dual-fluorescence immunocytochemistry was used to identify subpopulations of cells expressing the prolactin receptor and autocrine prolactin.

Results:

Δ1–9 as a single agent had no effect on the cell number in monolayer culture, but potentiated the cytotoxic effects of doxorubicin and paclitaxel. Doxorubicin accordingly induced expression of prolactin mRNA and protein in all five breast cancer cell lines tested. Δ1–9 alone inhibited the clonogenicity in soft agar of cell lines by ~90% and the mammosphere forming efficiency of six disaggregated primary ductal carcinoma in situ samples by a median of 56% (range 32% to 88%). Subpopulations of cells could be identified in the cell lines based on the prolactin receptor and prolactin expression.

Conclusion:

Autocrine prolactin appears to act as an inducible survival factor in a clonogenic subpopulation of breast cancer cells. The rational combination of cytotoxics and Δ1–9 may therefore improve outcomes in breast cancer therapy by targeting this cell population.

100 项与 Delta-19 相关的药物交易

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