Lovastatin: Drug May Fight Asbestos-Related Cancer
I was recently alerted to the existence of a high cholesterol lowering drug, Lovastatin, which has been showed to target and kill mesothelioma cells in a test tube (in vitro). The drug is manufactured by Merck. I asked several mesothelioma experts about Lovastatin and whether it is a viable option for patients today. The answer is no. The drug has not yet been fully tested in laboratory mice, nor has it been tested in humans with mesothelioma.
Dr. Schwarzenberger, an assistant professor of medicine at LSU with expertise in gene therapy, warns that it is "premature" to begin lauding Lovastatin as a viable treatment for mesotheliotics. See his reply below. He does note that "there is much excitement over angiogenesis inhibitors (metalloproteinase inhibitors, e.g. marimastat)." Based on Dr. Schwarzenberger's tip, we will keep our eyes and ears open and post any news we hear regarding the effects of these inhibitors and their availability in any Phase III clinical trials for mesotheliotics.
Dr. Schwarzenberger raises a good point that because mesothelioma is relatively rare, and drug companies target diseases that are more prevalent, it is difficult to fetch the resouces that are necessary to finance clinical trials. I have always been concerned about this. A drug company is not likely to sink millions of dollars to undertake the research without some prospect of a profitable return. My view is that the companies who are responsible for poisoning the patients in the first place -- the asbestos companies -- should be paying for this research. At the very least, the asbestos companies have a duty to mitigate their damage. But how many websites have you seen from members of the asbestos industry that offer to help asbestos victims find treatments for their preventable diseases and tumors?
Dr. Dan Sterman of the University of Pennsylvania, who is one of the world's leading researchers on gene therapy, agrees with Dr. Schwarzenberger that it is too early to begin touting Lovastatin as a panacea for mesotheliotics. See Dr. Sterman's comments below.
Roger
Dear Mr. Worthington,
Thank you for your message. I think its quite premature to release this study as a potential treatment for mesothelioma with only having in vitro data. Although it is carefully phrased ('may help patients") it probably raises hopes that cannot be fulfilled, at least at this point. During my fellowship at the NCI, Lovastatin was developed in phase I (toxicity study). A variety of cancers were accepted for treatment, although most of them were prostate. We didn't see any effects (other than side effects) and the development was stopped. However, the doses we gave were much higher than for its prescribed use as anti cholesterol drug (30 fold and higher). The principal investigator of the study was Dr. Charles Myers, now at UV Charlottsville, VA.
Nowadays, there is much excitement over angiogenesis inhibitors (metalloproteinase inhibitors, e.g. marimastat), and several companies are developing these compounds. At the recent ASCO meeting I was informed of one patient who had rapidly progressing meso, he has now stable disease (no progression) for one year since he was started on a metalloproteinase inhibitor. However, this is only one case.
Best regards,
Paul Schwarzenberger
LSU Medical School
Dear Roger,
We at Penn are always interested in new approaches to mesothelioma.
Remember, however, that this is extremely preliminary research that may have a long way before it reaches human application. Many compounds have killed cancer cells in test tubes and mice, but have failed in human trials. Be careful of the word "breakthrough."
Nonetheless, we may be interested in experimenting with Lovastatin ourselves and perhaps running a randomized trial with advanced stage mesothelioma patients.
Sincerely,
Daniel H. Sterman, M.D.
University of Pennsylvania Medical Center
The article that prompted my interest is as follows (posted by Reuters on May 21, 1998) at:
NEW YORK (Reuters) -- Lovastatin, a drug used to treat high cholesterol, may also help patients with the asbestos-related cancer mesothelioma, according to researchers at the University of Minnesota.
Malignant mesothelioma, a cancer of the lining of the chest, can appear years after exposure to asbestos. Although there are now strict controls on the use of asbestos in the US, many workers were exposed to the substance in the past, and increasing numbers of the cancer are being reported in the US. The disease does not respond to surgery, radiotherapy, or chemotherapy. Median survival after diagnosis is less than 9 months.
In a laboratory, Dr. Jeffrey B. Rubins from the Veterans Affairs Medical Center in Minneapolis, Minnesota, and colleagues treated mesothelioma cells and normal lung cells with lovastatin. The drug inhibits cell growth and has been tested as a treatment for other cancers. In the study, the mesothelioma cells treated with lovastatin stopped growing and started to die, a process known as apoptosis. But normal cells were unaffected.
"Lovastatin is a commercially available and clinically well-tolerated agent that reduces viability and induces apoptosis of mesothelioma cells, and may provide the basis for adjunctive treatments of patients with mesothelioma,"' the investigators write in the May issue of the American Journal of Respiratory and Critical Care Medicine, published by the American Lung Association (ALA).
The researchers are now studying lovastatin's effect on mesothelioma in mice, and are studying epidemiologic data to see if people who have taken lovastatin have lower rates of cancer, according to a statement issued by the ALA.
SOURCE: American Journal of Respiratory and Critical Care Medicine
1998;157:1616-1622.
Reut18:03 05-21-98
** POSTED MAY 27, 1998 **
Lovastatin Induces Apoptosis in Malignant Mesothelioma Cells (May 22, 1998)
Abstract
Malignant mesothelioma causes profound morbidity and nearly universal mortality that is refractory to conventional treatment with aggressive surgery, radiotherapy, or chemotherapy. We report that pharmacologic concentrations of lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, induced apoptosis in human malignant mesothelioma cell lines. Mesothelioma cell viability was decreased in a dose-dependent manner by lovastatin (5 to 30 microM). These effects were not reversed by exogenous growth factors or cholesterol, but were reversed by addition of 100 microM mevalonate, confirming that lovastatin affected mesothelioma viability by inhibiting mevalonate synthesis. Lovastatin appeared to decrease mesothelioma viability by inducing apoptosis, as indicated by morphologic changes, histologic evidence of nuclear condensation and degeneration, and flow-cytometric analysis of DNA content. Lovastatin's effects on cell viability were partially reversed in the presence of farnesol, and treatment of mesothelioma cells with a specific farnesyl-protein transferase (FTP) inhibitor decreased cell viability and induced morphologic changes indistinguishable from those caused by lovastatin. In addition, lovastatin-treated cells showed translocation of ras guanosine triphosphate (GTP)-binding proteins from membrane to cytosolic fractions on Western blots, suggesting that lovastatin's effects on mesothelioma were mediated in part by disrupting acylation of GTP-binding proteins. Thus, lovastatin is a commercially available and clinically well-tolerated agent that reduces viability and induces apoptosis of mesothelioma cells, and may provide the basis for adjunctive treatments of patients with mesothelioma.
Address: Department of Medicine, Veterans Affairs Medical Center,
University of Minnesota, Minneapolis, USA.
Author: Rubins JB; Greatens T; Kratzke RA; Tan AT; Polunovsky VA;
Bitterman P
Source: Am J Respir Crit Care Med, 157(5 Pt 1):1616-22 1998 May
More concerns raised about Lovastatin (May 28, 1998):
According to a leading microbiologist, the Lovastatin drug blocks degradative pathways for many proteins including growth-factor receptors but it is not clear that it would have a differential effect on mesothelioma cells. This researcher is concerned that the control cells were not normal mesothelial but normal lung cells which can be quite different. This is a very early report. Surely, it should be tested on mesothelioma cells growing in mice before it could be considered hopeful.