Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical usefulness of BRCA1 and BRCA2 mRNA levels in tumor tissues in the prediction of response to docetaxel (DOC) treatment has been studied in breast-cancer patients. Twenty-five patients with locally advanced breast tumors (n = 13) or locally recurrent tumors (n = 12) underwent tumor biopsy and were treated with DOC (60 mg/m2 every 3 weeks). BRCA1 and BRCA2 mRNA levels in the tumors were determined by real-time PCR, and the expression of 6 biological markers (P-glycoprotein, p53, erbB2, BCL2, MIB1, estrogen receptor-alpha) in the tumors was determined by immunohistochemistry. BRCA2 mRNA levels (0.547 +/- 0.200, mean +/- SE) of responders to DOC treatment were significantly (p < 0.05) lower than those of non-responders (1.538 +/- 0.358), but there was no significant difference in BRCA1 mRNA levels between responders (0.389 +/- 0.081) and non-responders (0.779 +/- 0.172). Tumors were dichotomized into groups with high or low BRCA2 mRNA levels according to the cut-off value of 0.13. The response rate (25%) of tumors with high BRCA2 mRNA levels was significantly (p < 0.01) lower than that (100%) of tumors with low BRCA2 mRNA levels. Positive predictive value, negative predictive value and diagnostic accuracy of the BRCA2 mRNA assay in the prediction of response to DOC were 100%, 75% and 80%, respectively. No significant difference was found between responders and non-responders in the expression status of any of the other 6 biological markers. These results suggest that BRCA2 mRNA levels in tumor tissues might be clinically useful in the prediction of response to DOC treatment in breast-cancer patients.
 ...
PMID:Decreased expression of BRCA2 mRNA predicts favorable response to docetaxel in breast cancer. 1140 Jan 19

Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSB) that are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumors in a xenograft model. Spontaneous BRCA1-defective mammary tumors gain resistance to PARP inhibitors through increased P-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1-defective PARP inhibitor-resistant tumors. We also show that 6TG could kill cells and tumors that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PARP inhibitor-resistant BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is also required for survival from mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in the repair of 6TG-induced DSBs as well as mismatch repair-independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy.
 ...
PMID:6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance. 2063 Oct 63

Pan- or multidrug resistance is a central problem in clinical oncology. Here, we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly resensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel, and doxorubicin. We propose that multidrug resistance is a multifactorial process and that mouse models are useful to unravel this.
 ...
PMID:BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance. 2551 78