Tuesday, March 26, 2013

Chronic Myeloid Leukemia (CML) and a Remarkable Drug to Treat It.

Chronic Myeloid Leukemia impacts approximately 5000 people a year.  It is characterized by the uncontrolled growth of a subset of circulating white blood cells (WBC).  The onset of this disease correlates with a particular genetic abnormality that has been well categorized.  The change in the genetic material is demonstrated by the appearance of the so-called “Philadelphia” chromosome.  This chromosome results from the anomalous exchange of genes between chromosome 9 and chromosome 22 – the human genome possesses 23 pairs of chromosomes one pair of which contains the genes that determine human gender XX (female) and XY (male).  This genetic rearrangement results in the juxtaposition of two genes namely, BCR and ABL.  The resulting gene combination, BCR-ABL is responsible for the production of a novel gene product that contributes to uncontrolled cell growth i.e. CML.

The realization of this mechanism opened the possibility that if the activity of the deleterious protein product could be curtailed, a cure of CML could be envisioned.  This particular approach is known as molecular targeting, for it targets a particular molecular substance known to play a critical role in the development of disease – in this case, CML.

When it became clear that the “offending” protein was a member of a class of proteins referred to as kinase enzymes, Drs. Zimmerman and Buchdunger tested a plethora of possible drug candidates to see what compound could precisely target this enzyme without adversely affecting any other cellular processes.  Their work proved rewarding; they ultimately discovered the efficacy of a drug given the name, Gleevec (imatinib).

The results have been very impressive.  As reported in the Journal of the National Cancer Institute (JNCI), CML patients who have been treated with Gleevec have gone into complete remission after two years of treatment and have been shown to have survival rates similar to the general population.  According to a statement released by the journal, “This study offers the first evidence that a disseminated cancer, not amenable to surgery, can be controlled to the point of giving patients a normal life expectancy.”

These results are extraordinary, yet they point to the efficacy of the molecular targeting approach.  This methodology may prove applicable to other heretofore treatment-resistant diseases. 

Friday, March 15, 2013

Stimulants, Opiates and the Human Brain

Chemical stimulants such as cocaine and opiates such as morphine profoundly influence behavior through their interaction with and alteration of brain chemistry.  Members of the opiate family of compounds are known to markedly reduce the experience of pain.  Of particular interest in this regard is the neurotrophic factor, BDNF – a direct product of brain chemistry.  BDNF plays a very important role in maintaining so-called “neural plasticity.”  This plasticity represents an intrinsic ability of the human brain to alter neuronal pathways and synapses – the junctions between nerve cells that allow the passage of electrical signals through the nervous system – in response to changes in behavior and the environment especially in regard to bodily injury.  This is a highly adaptive function of the brain that is often seen in the victims of stroke – allowing individuals to compensate for brain damage.

BDNF has been shown to play a key role in the kind of neural and behavioral plasticity that is induced by the use of cocaine and other stimulants.  Furthermore, it has been demonstrated that the mode of action of BDNF in this regard is intimately connected with the mesolimbic dopamine (DA) system that represents a key reward circuit in the brain.  Dopamine is one of major neurotransmitters in the brain that is involved in many diverse brain functions.  It is the irreversible loss of dopamine-producing cells that results in the symptoms associated with Parkinson’s disease.  The net result of the interaction of BDNF with DA system is the promotion of further actions of stimulant drugs.

Dr. Ja Wook Koo and his colleagues at the Fishberg Department of Neuroscience and Friedman Brain Institute at the Mount Sinai School of Medicine in New York have implicated BDNF in the mode of action of the opiate drug, morphine and have helped elucidate the mechanism through which it works.  In contrast to stimulants, opiates exert their effect on the brain through the promotion of DA signaling by the inhibition of ϒ-aminobutyric acid (GABA) – an important neurotransmitter in the brain that plays a role in regulating neuronal excitability through an inhibitory pathway.  The investigators have clearly shown that BDNF is, in fact, a negative modulator of morphine action.

This is an important finding in that is helps elucidate the mechanisms involved  with  brain-associated adaptations within the reward circuitry that occur with the use of morphine – a drug that is widely used to treat severe chronic pain especially at the end of life.