Doxorubicin

Italian researchers have found that the statin drugs, commonly used to reduce cholesterol, can be a useful adjunct to treatment of mesothelioma with doxorubicin.

Doxorubicin is one of the workhorses of modern chemotherapy.  It’s used in many types of cancer, including mesothelioma, but it’s of limited effectivness in mesothelioma, which is notoriously difficult to treat.

The researchers found that the mevastatin and simvastatin increased the accumulation of doxorubicin in the mesothelioma cells and increased the cytotoxicity of doxorubicin.  This might help refine and improve treatment of mesothelioma in the future.


The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guideline.

Ellis P, Davies AM, Evans WK, Haynes AE, Lloyd NS; Lung Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care.

McMaster University at Hamilton Health Sciences and Juravinski Cancer Centre, Hamilton, Ontario, Canada. vanderja@mcmaster.ca

BACKGROUND: This clinical practice guideline, based on a systematic review, was developed to determine which chemotherapeutic agents (or combinations of agents) show the highest response rates, improved survival, quality of life, or symptom control in patients with advanced malignant pleural mesothelioma. METHODS: A thorough systematic search of the literature was conducted for published articles and conference proceedings for applicable abstracts. Relevant trials, published as articles and abstracts, were selected and assessed. External feedback was obtained from Ontario clinicians, and the guideline was approved by the provincial Lung Cancer Disease Site Group. RESULTS: One hundred nineteen studies were eligible, including eight randomized trials and 111 phase II trials. The pooled response rates from phase II trials suggest that response rates with combination chemotherapy are higher than with single agents. Data from the largest randomized controlled trial demonstrated that chemotherapy with cisplatin and pemetrexed significantly improves response rates (41% versus 17%, p < 0.001), time to progression (5.7 months versus 3.9 months, p = 0.001), and overall survival (median, 12.1 months versus 9.3 months, hazard ratio = 0.77, p = 0.020) in comparison to single-agent cisplatin. A second trial demonstrated cisplatin and raltitrexed significantly improved median survival compared to single-agent cisplatin (11.4 months versus 8.8 months; hazard ratio = 0.76, p = 0.0483). Overall response rate (24% versus 14%, p = 0.056) was greater in the combination treatment arm, but this difference was not statistically significant. CONCLUSIONS: There is good evidence to recommend chemotherapy with pemetrexed and cisplatin for adult patients with symptomatic advanced malignant pleural mesothelioma. Such treatment should be administered with supplementation of vitamin B12 and folic acid. If pemetrexed is not available, cisplatin plus raltitrexed is a reasonable alternative.
 

Statins Reverse Doxorubicin Resistance in Mesothelioma Cells

 

NEW YORK JUL 12, 2006 (Reuters Health) - Statins reverse doxorubicin resistance in human malignant mesothelioma cells in culture, a finding that may lead to new clinical strategies to improve doxorubicin efficacy in this hard to treat cancer.

"The mechanism of statin-mediated inhibition of small G-protein function is the molecular basis of the drug-elicited reversion of doxorubicin resistance in human malignant mesothelioma cells," Dr. Amalia Bosia from University of Torino, Italy told Reuters Health.

Dr. Bosia and colleagues investigated the ability of statins to reverse resistance to doxorubicin in drug-resistant primary human malignant mesothelioma cells and the molecular mechanism behind the reversion, according to their report in the July 1st issue of the International Journal of Cancer.

Mevastatin and simvastatin significantly increased the intracellular accumulation of doxorubicin in the mesothelioma cells and increased the cytotoxicity of doxorubicin, the authors report.

These effects were completely abolished after the statins were incubated with mevalonic acid, the product of HMGCoA reductase, or with the nitric oxide synthase inhibitor L-NMMA.

The statins appeared to exert their effect by down-regulating active RhoA and RhoA-associated kinase activity and increasing phosphorylation and activation in mesothelioma cells, the researchers note.

Y27632 and toxin B also enhanced doxorubicin accumulation and cytotoxicity by way of increased nitric oxide synthesis in the mesothelioma cells, the results indicate.
 
Parthenolide, an inhibitor of IkB kinase-alpha activation, significantly reduced nitric oxide synthesis and doxorubicin accumulation in the presence of simvastatin, mevastatin, toxin B, and Y27632, the investigators say.
 
"To our knowledge, this is the first report showing a correlation between RhoA/Rho kinase inhibition, nitric oxide production and reversion of doxorubicin resistance," the authors conclude. "Our results could suggest new clinical strategies aimed to improve doxorubicin efficacy in the treatment of human malignant mesothelioma."
 
"We want to determine the therapeutic potential of statins in reverting the doxorubicin resistance of human malignant mesothelioma in a severe combined immunodeficiency mouse model of human malignant mesothelioma in vivo, in which malignant mesothelioma cells may be transplanted without rejection," Dr. Bosia said.
 
"A better knowledge of the whole molecular pathway involved in doxorubicin-resistance in malignant mesothelioma may allow the design of more specific and more potent drugs, with less side effects than statins," she concluded.
 
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