Monday, February 14, 2011

New drugs for old.

A number of drugs are finding new uses. Aspirin was developed as an analgesic, but it has largely supplanted from that role by paracetamol and ibuprofen. Today it is more likely to be used to prevent stroke or other thrombotic conditions. It is also suggested that it might help prevent pre-eclampsia of pregnancy, dementia and colon cancer. Raloxifen is used for osteoporosis after it failed as an oral contraceptive. Prozac flunked its trials as a hypotensive and Viagra didn't work in angina. The monoclonal antibody bevcizumab was developed to treat metastatic colon cancer, but it has found a new role in treating macular degeneration, one of the causes of blindness in the elderly.

Thalidomide, developed for morning sickness is now standard treatment for multiple myeloma. It also works in leprosy. The anti-gout medication allopurinol was originally developed as a cytotoxic drug. Bimatoprost was originally and anti-glaucoma drug but found more use to make eyelashes grow longer! Bromocriptine, an anti-Parkinson's drug, and Colesevelam, a cholesterol lowering agent, have both found a role in type 2 diabetes. Metaclopramide was originally used as an anti-emetic, then to speed up Barium follow-throughs in radiology and now as an anti-migraine medication. Alemtuzumab was originally used for T-cell leukemias and now is poised to make a difference in multiple sclerosis.

Homoharringtonine has been around for a long time as a treatment for CML. Of course it has been overtaken by imatanib and is seldom see these days. A paper has appeared in the 6th January Blood from MDACC demonstrating that homoharringtonine reduces the expression of Mcl-1 in CLL cells.

Mcl-1 is the major anti-apoptotic protein in CLL. It acts by preventing the pro-apoptotic proteins Bak and Bax from disrupting the mitochondrial membrane and thus initiating apoptosis. Strategies to inhibit the effect of members of the bcl-2 family include the anti-sense oligonuclotide, oblimersen, and the BH3 mimetics like Abt-263. Flavopiridol, roscovitine and SNS-032 all target Mcl-1, so homoharringtonine may well have a place in the treatment of CLL.


Wayne said...

In 2008 I was curious to know whether I had upregulated Mcl-1 due to the aggressive nature of my CLL that was at odds with FISH, IgVH mutation status & CD38 neg testing. I was told it was very hard to test for owning to a short life and I believe the location being most important in the nodes or marrow.

Would Mcl-1 knowledge have clinical utility today and are there more easily testable surrogates of Mcl-1 to tell if this is a feature of one's CLL?


Terry Hamblin said...

Homoharringtonine seems to work because of the short half life of Mcl-1, but this makes it hard to test for except in research labs. There are no acceptable surrogates.

Anonymous said...

Dr Hamblin,
What in your judgement does your list of repurposed drugs say about "evidence based medicine"? Will EMD inhibit finding such new uses? - - Bruce in Maine

Terry Hamblin said...

This might be a topic for a blog. There was an article in NEJM last week which looked at new uses for old and it suggested that publically funded universities were the major innovators in this way. When I was young some people thought me a maverick because I was always trying new things including plasma exchange for SLE, Sjoegren's syndrome, erythrocyte autosensitization, Crohn's disease, and certain types of deafness; leucapheresis for CLL, monoclonal antibody therapy for CLL and NHL, low dose ara-C for MDS and AML, Vitamin D for MDS, idiotype vaccination and DNA vaccines for NHL, marrow laundering with Campath, peripheral blood stem cell transplants for lymphoid malignancies; these were all pioneered in my department. I retired just in time; I would not be allowed to do these things now.