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1.INTRODUCTION

            Gene
transcription and DNA synthesis is strongly dependent to protein kinases which
have critical roles in signal transduction pathways for transmission of
information regarding extracellular or cytoplasmic conditions in nucleus, by
this way they affect the gene transcription.1  There are numerous of protein kinases
(around 550), on the other hand only few (130) protein phosphatases which
regulate the protein kinases activities.2

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            Protein kinase enzymes transfer phosphate from ATP to
amino acid on the substrate specifically. This phosphorylation process leads to
signal-transduction pathway activity including lots of biologic processes such
as cell growth, differentiation etc. and the function is shown fig 1. Studies
have shown that there are deregulated, overexpressed protein kinases in tumor
cells so the cancer treatments focused on this pathway and investigating
selective and specific pharmacologic inhibitors. Protein kinase receptor
inhibitors are popular investigating for cancer treatments that mimicking the
adenine portion of ATP with their flat aromatic structure.2 In
fig. 2 mechanism of protein kinase receptor inhibitor is shown schematically.

The most popular studies are on BCR-ABL tyrosine
kinase which is directly affecting CML (chronic myelogenous leukemia). CML is a
life-threatening cancer, affecting marrow. There are hematologic stem cell
disorder observed which is result of abnormal DNA synthesis. Up to 2000s, the
only treatment is thought marrow transplantation. It is quite risky and finding
proper donor is really hard. Thus, other treatments are tried to apply such as
chemotherapy with Ara-C, hydroxyurea and interferon. However, patients were
suffering from side effects, so the breakthrough drug, “Gleevec” is
represented.2,3

            Gleevec,
with other name is called “imatinib” is a tyrosine kinase receptor inhibitor
shown in fig.3 which is highly effective on CML and gastrointestinal stromal
tumors (GIST). Imatinib is approved by FDA for CML threatment in 2001 and
become a first-line treatment of CML in 2001.3

 

Fig 1. Phosphorylation Process2

 

Fig 2. Mechanism of tyrosine kinase
receptor inhibitor in CML3

Fig 3. Imatinib mesylate3

2.CHEMISTRY &
MECHANISM

Imatinib mesylate is formed by “2-phenylaminopyrimidine” as
a lead compound and all the series is named as “4-(4-methyl-1-piperazinyl)methyl-N-

4-methyl-3-4-(3-pyridinyl)-2-pyrimidinyl
amino-phenylbenzamidemethanesulfonate” by
screening techniques in medicinal chemistry.1

The lead compound 2-phenylaminopyrimidine is poor
specific and does not have high potency while inhibiting serine/threonine and
tyrosine kinases. Handling these problems 32-pyridyl group at the 32-position
of the pyrimidine is added, thus the cellular activity is improved. There are
other modifications for the enhancing activity through platelet-derived growth
factor receptor tyrosine kinase and serine/threonine kinase inhibition is
decreased with the same way.

            Additionally,
other inhibition activities through ABL tyrosine kinase and receptor tyrosine
kinase is obtained. Addition of N-methylpiperazine aimed to enhance the water
solubility as a polar group and also improving of bioavailability is obtained.1

            Imatinib
inhibits the ABL and its derivatives v-ABL, BCR-ABL and EVT6-ABL. In in vitro
studies, the IC50 values is obtained as 0.025 µM. Its activity
against the PDGFR and KIT are similar but IC50 values showed that
other tyrosine and serine/threonine kinases have higher value at least 1000
times higher means that imatinib is a more selective agent than others.According
to cellular studies, imatinib inhibited specifically the myeloid cells
proliferation expressed BCR-ABL.1

 

 

3.PHARMACOKINETICS

In
experimental studies, it is found that 2 to 4 hours is required to reaching
maximum plasma concentration of imatinib and 98% mean absolute bioavailability
is obtained for capsule formulation. After oral administration in healthy
volunteers, active metabolite elimination half-life is 18 hours and N-desmethyl
derivative elimination is given as 40 hours. It is observed that rising the
dose ends up with increase of AUC. When the repeating dose and food
administration is investigated, there is no important change of
pharmacokinetics.1

4.SYNTHESIS OF
IMATINIB MESYLATE

Synthetizing
imatinib mesylate includes 12 steps in manufacturing process in shortly by
NOVART?S. The synthesis steps are shown in fig.4.3

1: imatinib mesylate

6: 3-acetylpyndine

7: 3-dimethylamino-1-(3-pyridyl)-2-propen-l-one

8: 2-amino-toluene

9: 2-amino-5-nitrophenylguanidine

10: nitrophenylpyrimidine

11: aminophenylpyrimidine

 

 

Fig 4. Synthesis steps of imatinib
mesylate3

5.DISEASES

5.1. Chronic
Myeloid Leukemia

            BCR-ABL is a fusion
protein which is the result of translocation in Philadelphia chromosome of 9
and 22, ends up with leukemiogenesis. As imatinib is used, meaningful and rapid
inhibition of this protein is observed, thus imatinib is used for treatment of
CML. When it is compared with interferon-alpha (INF-?) for patients, imatinib
reduced the hematological response with the 95.3% and cytogenetic response was
found as 73.8%. When MMR (major molecular response) and progression-free
survival (PFS) is investigated 60 months following, 97%PFS for 12 months and 89%
PFS for 60 month is reached. Better results are obtained from early molecular
response as predicted. Despite all accomplisments, resistance to imatinib is a
major problem. According to patients examination, initial responses are lower
in advanced-phase disease and responses were nonpermanent. Primary resistance
is described as inability to reach CHR at 3 months and MCR at 6 months. It is
considered that the differential of drug metabolism or drug transport can be
the causes.4

5.2. Gastrointestinal Stromal Tumors

It is result of mesenchymal neoplasms of the GI tract. Expression of
c-KIT in tumor cells activating KIT mutations and PDGFRA mutations. Imatinib
has reducing effect on this disease and inhibits tyrosine kinase activity of
KIT. There is also positive effect on the treatment of unrespectable or
metastatic GIST. For this disease different dosing regimens are examined with
746 patients and there is no significant difference between 800 mg and 400 mg
drug dosing for healing. The similar results are obtained for both two dosage
both progression-free survival and overall survival.4

5.3. Philadelphia Chromosome-positive Acute
Lymphoblastic Leukemia

Adult ALL patients has an abnormality on Philadelphia
chromosome. It is a new diagnosis for ALL and it is age dependent disease, with
increasing age it gives unfavorable prognosis. It differs from CML as the
different sized proteins caused by the abnormality of Philadelphia chromosome
which has translocation on 9 and 22 chromosomes. The result of this
translocation is producing fusion gene which express highly BCR-ABL and it ends
up different sized p190 and p210 proteins. While CML cases generally produce
p210 predominantly, ALL patients synthesize Ph-positive p190 protein. Imatinib
is a promising treatment strategy for ALL patients also. 4

5.4. Malignant Melanoma

Malignant melanoma is a disease which is a neoplasm of
melanocyte, following increasing trends each year as 4%. Certain treatment
strategy is generally surgery. It is life-threating cancer and patients suffering
from MM can survive 12 months or less in advanced level of cancer. There are
mucosal ( on sinuses, mouth or vagina) or 
cral melanomas (non-hairy palm, soles nail beds) and the genetic
alterations and biologic behavior are changing in these types. In latest
studies there are KIT-activating mutations are observed. Due to KIT-activating
mutations imatinib is a different strategy for treatment of disease. 4

There are other diseases such as recurrent epithelial
ovarian cancer, anaplastic thyroid cancer, chordoma, AIDS-related kaposi’s
sarcoma in which imatinib is a new and promising strategy and the studies are
still remaining on these diseases. 4

6. CLINICAL CASES
& FDA APPROVEL REPORT

Before FDA approvel to
Gleevec, the experimental studies on real patients have done. For this reason,
532 patients with CML which have had IFN-? therapy and have no response. At the
beginning patients have had 400 mg imatinib mesylate dose. Patients are
followed for 2 years with the stated dosage of imatinib mesylate and after 2
years therapy, 85.4% of patients were free of progression to accelerated phase
or blast crisis.5 

Imatinib is a breakthrough
drug for cancer patients but there are also patients, suffering from side
effects and lost their lives. The reports belongs to these patients will be
discussed as following.6

            Case 1: Patient had
acute hepatitis during imatinib therapy.

Table 1. Case 1 imatinib side effect therapy

Age

53

Sex

Female

Disease/ Abnormality

Gastrointestinal stroal tumor

History

No history of liver disease before imatinib

Severity

jaundice, hospitalization, ascites and hepatic encephalopathy

 

 

Case 2: Patient
suffered liver failure due to imatinib

Table 2.Case 2 patient with imatinib therapy

Age

51

Sex

Female

Disease/ Abnormality

CML

History

No history of liver disease before imatinib

Severity

acute liver failure and death

 

 

 

 

 

Case 3: Patient suffered from hepatitis B

Table 3.Case 3 patient uses imatinib mesylate

Age

48

Sex

Male

Disease/ Abnormality

CML

History

No history of liver disease before imatinib

Severity

Liver transplantation

 

 

 

 

 

 

 

7.
CONCLUSION

            Imatinib
is a breakthrough drug and has FDA approvel since 2002. It is a tyrosine kinase
receptor inhibitor which is selective the tumors express highly BCR-ABL. It has
wide usage area regarding tumors in human body and gives promising results to
prevent the progression of tumors.

            Although
it has many benefits on patients who suffer from different cancers and have no
effective therapy, it has serious side effects on patients. It is generally
effecting liver and causes multiple organ failure on patient and finally death. 

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