GIST Support WikiLet's say you have cancer cells sitting on a nice wrought iron and wood slat bench by the bus stop. These are dormant cells, just sitting there...maybe Forrest Gump is sitting next to them, telling them about being a shrimpin' boat captain, but for the most part these GIST cells are just sitting on the bench. These cells in "biology speak" are dormant. They aren't in "cell cycle" which means they aren't doing anything---just sleeping. Zzzzzz
Then you have the large majority of the GIST cells in your tumor, and these are active busy cells, that are in "cell cycle" meaning that they are walking across the street in front of the bus stop to get somewhere else...the coffee shop on the other side of the street--so to speak. A cell in "cell cycle" is growing fatter, thinking about making new DNA, and getting ready for cell division--mitosis.
Gleevec is the city bus. It comes barrelling down your GI tract,absorbed into the blood stream, and down the city street of your body, where it comes at full spead towards the bus stop where it runs over and wipes out the majority of stupid GIST cells who did not look before they crossed the street. These are the guys in "cell cycle".
Meanwhile, the few stray GIST cells sitting on the bench listening to Forrest Gump tell about his running days...are not hit and killed by the city bus of Gleevec. They are "dormant".
BUT--once and a while one of them grows weary of being dormant, sitting on the bench listening to Forrest Gump, and thinks that he too would like to wake up, go in cell cycle and cross the street...And when he does this, he gets wiped out by the city Bus called Gleevec.
So...what you have is a "biphasic" kill situation...the masses get killed by the Gleevec bus up front, as they were busy in cell cycle trying to cross the street. The few stray sitting on the bench will over the years, one by one wake up, try to cross the street and get hit by the Gleevec bus. This is a SLOWER rate than the first kill rate...the gradual evacuation of the bench by the bus stop. It may take more than seven years.
This has all been worked out mathematically and in "biology speak" for chronic myelogenous leukemia and Gleevec. It has been written up and posted in medscape. You can read it below. As you read it, just remember it is just a fancy boring way to describe the bus stop scenario, but in boring language.
If you have GIST cells left in your body, a year of adjuvant Gleevec is not going to cure you. Nor two years. Now it may reduce the number of tumors when you do have a recurrence, but these tumors might also be enriched in the secondary mutations that are resitant to Gleevec--like exon 17 KIT mutations--so are you better off???.
If I was high risk for recurrence, I would probably go on adjuvant Gleevec and stay on it indefinitely. We already know from Pam L and Lee Ann that those who stay on it can grow resistant tumors, but these seem to be single tumors that can be removed surgically.
http://www.medscape.com/viewarticle/563748
Imatinib Can Eradicate CML Under Certain Circumstances
Roxanne Nelson
Medscape Medical News 2007. © 2007 Medscape
October 4, 2007 — Imatinib (Gleevec, Novartis) is used as a first-line treatment for chronic myeloid leukemia (CML), but while it frequently puts the disease into remission, patients often relapse when treatment is ended. However, the results of a study published in the October 3 issue of PLoS ONE demonstrate how imatinib may be able to cure CML under certain circumstances.
CML is associated with a chromosomal translocation that produces the Philadelphia chromosome, which generates a chimeric tyrosine kinase called BCR-ABL. It is believed that the initiation and progression of CML are driven by the Philadelphia chromosome. Imatinib mesylate, an inhibitor of the BCR-ABL tyrosine kinase, has improved outcomes in CML, especially when the treatment is started during the chronic phase of the disease.
Patients treated with imatinib typically have their blood cell counts return to normal levels, and levels of the BCR-ABL gene sometimes become undetectable. But even though patients generally relapse when imatinib is stopped, study authors Natalia L. Komarova, PhD, and Dominik Wodarz, DPhil, both from the University of California, Irvine, point out that recent data have shown that that is not always the case. Some patients have remained in remission for as long as 2 years after treatment ended, indicating that these individuals perhaps may have been cured of their disease.
Using a mathematical model, the researchers investigated the effect of cellular quiescence on the outcome of therapy and how it might influence the kinetics of patient response to imatinib. "This happens in stem cells and also in primitive cancer cells that have stem cell–like traits, also referred to as cancer stem cells," said Dr. Komarova, an associate professor of mathematics. "Importantly, the drug imatinib does not affect quiescent cells while it removes active cells.
"Cells in a quiescent state therefore provide a problem for therapy, and they account for the observation that the decline of the cancer cells can be very slow in the long term," she told Medscape Oncology in an interview.
According to their models, treatment initiation can cause varying patterns of tumor cell decline. These include a biphasic decline, a 1-phase decline, and a reverse-biphasic decline. The biphasic decline results in a rapid initial phase that approximately correlates to the eradication of cycling cells by imatinib, and this is followed by a second phase that is characterized by a slower rate of CML cell decline. The second phase corresponds to the awakening and subsequent death of quiescent cells. However, this pattern is not universal, and the model predicts alternative patterns of cell decline.
"The quiescent cells do 'wake up' spontaneously, and when this happens, Imatinib can remove them," said Dr. Komarova. "The long-term response to treatment is dictated by the 'waking-up kinetics' in the model, and based on this, the model prediction is that you can eventually drive the cancer to extinction in the patient."
The mathematical formula, therefore, dictates the length of time needed to treat to achieve eradication of the cancer cells.
The researchers also evaluated the effect of cellular quiescence on the evolution of drug resistance. "If the cancer is treated with a combination of 2 or more drugs, then quiescence increases the chances that resistant cells will emerge," said Dr. Kamarova. "Based on our parameters, we can calculate the number of drugs required to prevent the emergence of cells that are resistant to the treatment regime and to ensure a successful response."
Based on their mathematical models, she summarized, they were able to predict the length of time needed to treat to achieve eradication of the cancer cells, assuming that cellular quiescence was the limitation and that there were no resistant cells interfering with treatment efficacy.
"We also predicted how many drugs should be used in combination, to make sure that there are no mutant cells that are resistant to the treatment regime in use," Dr. Kamarova said. "To get actual numbers out of the formulas, you need to know the parameter values that will have to be determined by experiment, measuring things like the rate of cell division, cell death, mutation rate, and the kinetics that determine how fast cells go to sleep and wake up. This would be the next step."
This work was supported in part by a National Institutes of Health grant to both authors and a Sloan Fellowship to Dr. Kamarova.
PLoS ONE. 2007;2:e990. Abstract