Thursday, March 26, 2009
Gleevecs
On p. 183, Carroll describes Gleevec or Imatinib, a drug that inhibits the ABL kinase protein by binding to it, like a toxin. Describe what happened to the effectiveness of the drug, why this happened, how and where we've seen this before, both in the book and in class, and then describe some future treatments that are possible for cancer, and explain how they would overcome the problems described.
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ReplyDeleteGleevac was administered to patients with chronic myelogenous leukemia, or CML for short. Eventually, due to mutation and selection, CML developed a resistance to Gleevac and the overall resistance decreased. This is due, in part, to the fact that Gleevac is a toxin to DML cells. Sean Carroll discussed how garter snakes from Oregon evolved resistance to TTX and how malarial parasites develop drug resistance; thus, “CML cells will be more resistance to Gleevac because of additional mutations that have occurred in those cells” (Carroll 183). Mutations are generally defined as changes in the genetic material of a cell or virus and have allowed CML to gain resistance to Gleevac.
ReplyDeleteTTX is defined by Carroll as “a potent blocker of another type of ion channel, sodium channels, that are critical for nerve function. . . [and] causes paralysis, respiratory distress, abnormal heartbeats, and in modest doses, death” (Carroll 166). The Oregon rough skinned newt has large doses of TTX in its skin and thus, is highly deadly; this is evidenced by the man who ingested a newt in 1979 and consequently died in twenty-four hours. Another organism that has large doses of TTX in its body is the puffer fish. Carroll also describes the case of the newt and the man as an “evolutionary arms race” (Carroll 166). The newt’s enemy in nature is the common garter snake, also called Thamnophis sirtalis, because it has a resistance to the newt’s TTX.
TTX levels and resistance to TTX varies in both newts and garter snakes, respectively. This suggests that the two species coevolved with one another. This is an example of the biological theme evolution, or in this case, coevolution, where organisms change themselves in order to increase their chances of survival. The Campbell text book says that animals have influenced the evolution of terrestrial plants. This is due to the fact that the animals’ diets affect natural selection amongst plants; for example, “animals crawling and foraging for food on the forest floor, natural selection must have favored plants that kept their spores and gametophytes far above ground, rather than dropping these crucial structures to within reach of hungry animals on the ground” (Campbell), which may have then favored the evolution of flying insects. Additionally, herbivores assisted plant in dispersing by becoming carriers of their seed and pollen. Overall, the reproductive success of both organisms improved. The Oregon rough skinned newt and the garter snake must have similarly coevolved; the newt is able to survive and the garter snake is able to eat from a large food source despite the fact that it may experience symptoms of TTX poisoning such as becoming flaccid and an inability to hold their head steady. Also, the offspring of the snake will develop this resistance. Resistance can leave “very strong marks on the genetic makeup of populations”, such as CML.
There is an example of resistance among HIV-infected patients. Nicholas Balaker writes about a few select people that are infected with HIV but still maintain a low viral load and are never sick (source: http://discovermagazine.com/2009/jan/054); they are called “elite supressors”. These people may have immune systems capable of developing resistance to the virus, maybe due in part to contracting a weaker strain of HIV.
Charles Sawyers and his colleagues examined the CML’s resistance to Gleevac in cancer patients (Carroll 184). They found in that the mutations developed in the genetic makeup of CML on the ABL kinase gene, the same mutation occurred in patients that had Gleevac resistant CML. The same mutations indicate that certain mutations do in fact help CML resist Gleevac and ‘survive’. Specifically, the mutation “[caused] the replacement of a threonine in the ABL protein with an isoleucine” and changes the shape of the “pocket” on the ABL kinase that Gleevac latches onto normally; this is a relationship between structure and function; because the shape of the ABL kinase Gleevac receptor was changed, Gleevac was unable to bind and thus, the protein function is blocked.
New means are being developed to combat the Gleevac-resisting ABL kinases. Sawyer and others showed another ABL kinase inhibitor called BMS-354825, which is resistant against most Gleevac-resistant kinases; by developing a resistance the new ABL kinase inhibitor can act in a similar fashion as to how the garter snake coevolved with the newt, fighting resistance by changing, or coevolving. This is possible for a second therapy treatment for patients that relapse after a Gleevac treatment and also brings up the possibility of combination treatment. Genetic specificity in terms of treating patients’ tumors applies to resistance evolution and will probably increase success rates of recovery from different types of cancer.
Imatinib has increasingly been used as a drug to fight cancer and the tumors that develop as a result of uncontrolled cell division, which is controlled in the body by a molecule called cyclin. In the cell cycle, cyclin is the protein that binds to the kinase (the enzyme that drives the cell cycle) in order to activate it. The involvement of several Cdk proteins and cyclins are necessary to move past the the G1 checkpoint, from where the cell will normally complete the division. However, when a cell undergoes transormation (the process that converts a normal cell to a cancerous cell), the cell no longer appears to need the growth factors, so they grow continously. In people with hepatocellular carcinoma, the immune system produces antibodies in response to the detection of cyclin B1. After detection, it invokes such a response because in cancerous cells, the cyclin behaves in a manner similar to an antigen would. It is known that cyclin B1 in fact causes this behavior of the immune system because in a test, the researchers studying cyclin and its function as a tumor antigen were not able to find any antibodies that were created in response to cyclin B1 in healthy subjects. After recognition, the immune system synthesiszed various lymphocytes to fight the tumor. In most cases, the immune system is able to fight off the cancerous cells within two years. However, if the immune system is not able to overcome the threat of the cells, the cells spread through a process called metastasis.
ReplyDeleteTo continue, the Philadelphia chromosome is a chromosomal abnormality. While it is normally associated with chronic myelogenous leukemia, it can also be linked to acute lymphoblastic leukemia (ALL), as well as acute myelogenous leukemia (AML).
Relating all of this back to imatinib, according to the American Society of Hematology (ASH), more than twenty five percent of all ALL cases include Philadelphia chromosome positive (Ph+) ALL. ALL is defined as the overproduction of lymphocytes by the bone marrow, as it results in the decrease of available healthy white blood cells, red blood cells, and platelets. In its study of the clinical features of Ph+ ALL, the ASH noted that the chance at acquiring this disease increases along with age. Unfortunately, the chance at long term survival after the application of chemotherapy is at a measly 10%. For that reason, allogeneic stem cell transplantation is considered to be the top choice for treatment of adult Ph+ ALL. An allogeneic stem cell transplantation is when a person receives blood forming stem cells from a genetically similar individual (such as a brother or sister). In order to try to increase the chance of a sucessful fight against cancer, the use of imatinib has also been tested, and the ASH recorded synergy between synergy and chemotherapy, suggesting that if there is a way to use the two in conjunction with each other efficiently in the future, there may be a greater chance for survival.
Imatinib works by inhibiting the effects of tyrosine kinase enzymes. It binds to the active site, thereby acting as an allosteric inhibitor, decreasing the amount of activity. While there are a number of tyrosine kinase sites throughout the body, imatinib is specific for the tyrosine kinase at the location in the Abelson proto-oncogene. The overall effect of imatinib is to inhibit the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates through competitive inhibition (binding to the allosteric site).
http://asheducationbook.hematologylibrary.org/cgi/content/full/2005/1/118
http://www.cancer.gov/cancertopics/pdq/treatment/adultALL/Patient
http://en.wikipedia.org/wiki/Imatinib
http://en.wikipedia.org/wiki/Philadelphia_chromosome
http://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia
http://cancerres.aacrjournals.org/cgi/content/full/66/1/6?ck=nck
http://en.wikipedia.org/wiki/Cancer