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DASATINIB: A DOUBLE-EDGED SWORD

by Selleckchem | Apr 25 2012

The demand for advance and innovative therapeutic tools has always been in high level for the efficient treatment of various kinds of cancers. The cancers that are highly proliferative and metastatic in nature have put an additional stress on the designing and discovery of a medicine or drug which promises better results. Mostly they adapt such mutations which tend them to remain unaffected to further treatment as a result evading the effects of drugs targeting them. High level toxicity is another big problem related to chemotherapy. For the treatment of blood cancer, Imatanib is found to be the best example of above mentioned statement. The reason that lead to the discovery of a better, less toxic and an efficient drug for treating white blood cell cancer is actually the resistance developed against Imatinib in the leukemic cell lines and its higher level of toxicity. As a result a new drug named Dasatinib BMS-354825 was developed for the treatment of leukemia cell lines and this drug is named after the scientist who discovered it, Jagabandhu Das. It has entered the horizon of fame and success and now found to be a better replacement of Imatinib and has proved to be a good therapeutic tool developed by Squibb for the treatment of tumor and is being sold now by the name of its brand Sprycel [1].

EFFECT OF DASATINIB ON SRC AND ABL KINASE PROTEINS:
Dasatinib is a very small molecule which is a dual RTK inhibitor molecule that means Dasatinib is reactive against two different kinases rather than a single one. Various suppliers Dasatinib provide this inhibitor and any one can buy Dasatinib from them by paying the amount around 50 dollars for 500 mg packing. The solubility Dasatinib is 200 mg/ml in DMSO but it is not soluble in water and ethanol. Dasatinib SRC inhibitor is an orally administered medicine. Dasatinib IC50 for SRC and ABL tyrosine kinase enzymes is 0.55 nM and 3 nM respectively for the Dasatinib SRC inhibitor and ABL family tyrosine kinases [2]. Dasatinib is greatly demanded to treat different types of cancers due to its ability of acting as a multi kinase and it is also an already approved medicine for the treatment of the patients of Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloma leukemia that are resistant to Imatinib [3-5] as it gives promissing results for Ph+ ALL and CML patients in their pre-clinical trials.

MODE OF ACTION OF DASATINIB:
In Dasatinib BCR-ABL inhibitor and the other members of Src family for instance Eph kinases, Src, c-Kit etc a variying specificity of inhibition has observed that depends upon the kinase type. In in vitro models the mode of action of Dasatinib has proved it three hundred times more efficient in comparison to Imatinib [6] hence got approved as a replacement for Imatinib. A study that describes properties of Dasatinib Src inhibitor showed that due to specific Dasatinib structure, it has high potential to react with various forms of ABL-BCR, hence making it more effective against Imatinib-resistant cell lines [7]. Dasatinib has the ability to bind more efficiently to the Imatinib-resistant cells regardless of the type of mutation they adapted. Dasatinib has found to inhibit CrKL phosphorylation in case of CML culture system that focused on its mode of action in these cell lines [1]. By using its property to block Src kinases, Lyn and SFKs and the down regulation of signaling pathway of p130CAS, Dasatinib’s efficacy against human prostate cancer was also studied [8]. It has also been found to be effective against of non-small cell lung carcinoma cell lines and head and neck cancer by causing the cell cycle arrest [9] hence adding various dimensions to its mode of action.

DASATINIB IN CLINICAL TRIALS
The in vitro treatment of the cell lines of breast cancer is very difficult due to some of the physiological traits like no progesterone, no HER2 or no estrogen. So according to some pre-clinical studies the special dual kinase activity of Dasatinib has found to be really valuable and efficient for aforementioned cell lines that are triple negatives [10]. A clinical study of phase I for the CML patients resistant for Imatinib has revealed complete hematological responses for maximum patients [11] also with some quite tolerable and easily manageable side effects. A phase II Dasatinib clinical trial for Philadelphia–positive ALL patients has proved it for its efficacy and safety [12]. Another phase II clinical study has proved this drug to be less toxic, have minimum level of non hematologic toxicity and progression-free survival in patients suffering from CML [13]. In a clinical trial of phase III, Dasatinib has proved itself more efficient along with more less level of toxicity in CML patients resistant to Imatinib [3, 14]. The reasonable Dasatinib price warrants the manufacturer’s attention.

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.
6. O’Hare, T.e.a., In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib resistant Abl kinase domain mutants. . Cancer Res, 2005. 65: p. 4500-4505.
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.