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A DOUBLE-EDGED SWORD: DASATINIB

by Selleckchem | Mar 29 2012

For the proper treatment of different types of cancers, there has always been a great demand of new and innovative therapeutic options. Those cancers are mostly highly metastatic and proliferative , and this thing puts an additional stress upon the discovery or designing of a drug which gives promising results. They most often develop some mutations which make them unaffected to on-going treatment hence evading the effect of medicines which target them. High toxicity level is another major problem related to chemotherapeutics. Imatanib is one of the prominent examples of above described statement which was in use for the treatment of leukemia. The high level of toxicity and the resistance developed against Imatanib in leukemic cell lines has led to the discovery of another efficient and less toxic drug for treatment of WBC carcinoma. Dasatinib BMS-354825 is such a drug named after its inventor Jagabandhu Das. It enters the horizon of success at this stage hence found to be a good replacement therapeutic agent developed by Squibb for the treatment of cancer and is sold now under the name of brand Sprycel [1].

DASATINIB AFFECTING THE SRC AND ABL KINASES:
A small molecule of Dasatinib is actually a dual RTK inhibitor which means that it is reactive against not only1 but 2 different kinase enzymes. Different suppliers Dasatinib provide this drug and one can purchase Dasatinib by paying 50 dollars for a 500 mg vial. Dasatinib gives 200mg/ml solubility in DMSO solution but it is completely insoluble in ethanol and water. This Dasatinib SRC inhibitor is orally administered. Tyrosine kinases of ABL family and Dasatinib SRC inhibitor has Dasatinib IC50 for ABL tyrosine kinase enzymes and SRC, 3 nM and 0.55 nM respectively [2]. Due to its property of multi kinase inhibition, Dasatinib is demanded for treatment of many types of tumors and it is an already approved source of treatment for patients of chronic myeloma leukemia and Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) which are now resistant to Imatinib [3-5] due to its promising effects in pre-clinical testing of CML and Ph+ ALL disease models.

DASATINIB: MECHANISM OF ACTION
Dasatinib Src-BCR-ABL inhibitor and all other Src family members like c-Kit, Eph kinases, Src etc has shown varying inhibition specificity for them which depends upon the type of kinase. Mechanism of Dasatinib in in vitro models has made it 300 times more efficient as compared to Imatinib [6] and thus took an approval for the replacement of Imatinib. According to a study describing the physiological properties of Dasatinib ABL inhibitor reveals that it has high potency due to its specific structure having the ability to react with different forms of BCR-ABL, hence make it more valuable against the cell lines resisitant to Imatinib [7] as it has the capability to bind efficiently to the resistant cell lines irrespective of the mutation they adapt. Dasatinib was found to be inhibiting phosphorylation of CrKL in chronic myeloma leukemia culture system which has focused on its mechanism of action [1]. Its efficiency against prostate cancer in human was also observed by its property of blocking Lyn, Src kinases and SFKs and down-regulating the signaling of p130CAS [8]. Dasatinib has also shown to be very effective against cell lines of non-small cell lung carcinoma and neck and head cancer by stimulating arrest of cell cycle [9] hence add different dimensions to its mode of activity.

DASATINIB: CLINICAL TRIALS
As we know that in vitro treatment of breast cancer cell lines is very difficult because of some physiological traits (no progesterone, no estrogen, no HER2) so according to a pre-clinical study, the dual kinase inhibition property of Dasatinib was found to be very effective for such aforementioned triple negative cell lines [10]. A phase I clinical trial on Imatinib-resistant CML patients has shown complete hematological responses in maximum number of patients [11]along with some side effects which were quite tolerable. In patients of Philadelphia–positive ALL, a clinical study of phase II has proved it to be safe and effective [12]. It was also proved to be a less toxic, progression-free survival and showing minimum nonhematologic toxicity in case of CML patient under clinical trials of phase 2 [13]. According to a phase III clinical trial, Dasatinib has shown its efficiency with less toxicity level in Imatinib-resistant patients of CML [3, 14]. Dasatinib’s reasonable price warrants the attention of manufacturers.

REFERENCES:
1. Copland, M.e.a., Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood, 2006. 107: p. 4532-4539.
2. Lombardo, L.J.e.a., Discovery of N-(2-chloro-6-methylphneyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in pre-clinical assays. J. Med. Chem., 2004. 47: p. 6658-6661.
3. Hochhaus, A.e.a., Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood, 2007. 109(6): p. 2303-2309.
4. Cortes, J.e.a., Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood, 2007. 109: p. 3207-3213.
5. Guilhot, F.e.a., Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood, 2007. 109: p. 4143-4150.
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7. Tokarski, J.S.e.a., The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants. Cancer Res, 2006. 66(11): p. 5790-7.
8. Nam, S.e.a., Action of the Src Family Kinase Inhibitor, Dasatinib (BMS-354825), on Human Prostate Cancer Cells. Cancer Res, 2005. 65: p. 9185.
9. Johnson, F.M.e.a., Dasatinib (BMS-354825) Tyrosine Kinase Inhibitor Suppresses Invasion and Induces Cell Cycle Arrest and Apoptosis of Head and Neck Squamous Cell Carcinoma and Non-Small Cell Lung Cancer Cells. Clin Cancer Res, 2005. 11: p. 6924.
10. Finn, R.S.e.a., Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Research and Treatment, 2007. 105(3): p. 319-326.
11. Talpaz, M.e.a., Dasatinib in Imatinib-resistant Philadelphia chromosome-positive leukemias. N. Engl. J. Med., 2006. 354(24): p. 2531-41.
12. Ottmann, O.e.a., Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood, 2007. 110(7): p. 2309-2315.
13. Kantarjian, H.e.a., Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood, 2007. 109(12): p. 5143-5150.
14. Shah, N.P.e.a., Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia. Journal of Clinical Oncology, 2008. 26(19): p. 3204-3212.