| Ch 11 | Page 12 / 16 | |
| Cancer other treatment |
Imatinib mesylate or Gleevec | |
Chronic myeloid leukaemia (CML) is characterised by the expansion of tumour myeloid clones, which maintain their maturation ability. At the preterminal phase, the leukaemia cells loose this capacity and lead to acute highly chemoresistant leukaemia.
A specific cytogenetic characteristic of such chronic leukaemia is the Philadelphia chromosome which is a reciprocal translocation between chromosomes 9 and 22 t(9;22)(q34;q11).
The molecular consequence of this translocation is the fusion of oncogen c-abl (Abelson mouse leukemia proto-oncogene) from chromosome 9 with sequences of chromosome 22 near to the breakpoint cluster region (or bcr). The new gene is called abl-bcr.
The C-abl gene codes for a tyrosine kinase more or less bound to receptors. Bcr-Abl tyrosine kinase activity is constitutively increased in CML cells, affecting numerous signal transduction pathways that are essential for leukaemic transformation, including increased cellular proliferation, antiapoptotic effects, and adhesion defects.
As early as 1988, specific inhibitors of tyrosine kinases were discovered: 2-phenylaminopyrimidine can conduct to synthesis of new compounds which have been studied for their interaction with ATP receptors of tyrosine kinases (especially kinases from PDGF: platelet derived growth factor). STI-571 was shown to be a powerful and selective inhibitor of tyrosine kinase abl. In the absence of tyrosine kinase activation, no phosphorylation of the substrates implied in cell proliferation occurs and cell division is stopped.
Imatinib mesylate (Glivec or Gleevec™) is prescribed orally at a dosage of 400 to 600 mg. During the chronic phase, the remission rate is very high (up to 90%) with a complete clearance of the cytogenetic abnormality (Philadelphia Chromosome) in about 40% of these cases. This remission can last for long periods. If no response is observed with this dosage, a higher dosage may be used (up to 800 mg).
During the blastic transformation of Chronic Myeloid Leukaemia (where survival is generally around 3 months), approximately 50% of patients respond, 10% of whom have a complete cytogenetic response. Median survival is 8 months, but 30% of patients live longer than 15 months.
Some other tumours, for which tyrosine kinase activity is increased, might respond to this specific inhibitor.
Gastric intestinal stromal tumours (GIST) ) express a mutation of c-kit at their cell surface with a permanent stimulation of this proto-oncogene. They respond remarkably to Imatinib mesylate (about 60-70%) whereas classical chemotherapy is almost inefficient. Certain unresectable tumours have been known to completely disappear. However, unfortunately, most of these remissions are incomplete with relapse occurring after a few months. No specific immunohistochemistry has been found to predict tumour responsiveness.
Among other potentially sensitive tumours, small cell lung cancer, myelomonocytic leukaema and glioblastomas (which often bear an autocrine self stimulation to PGDF) are currently under study
The toxicity of Imatinib mesylate is low: nausea, diarrhoea, myalgias, periorbital oedema, various skin rashes.
Imatinib mesylate generally has minor medullar toxicity (except when treating the blastic crisis of CML). In this situation, intense leukopaenia may be observed: all of the granulocyte precursors bear the chromosomal abnormality and activation of tyrosine kinase, thus strongly reacting to the drug. Normal stem cells need a given time before reactivation.
When treating GIST, tumour necrosis may occur with massive gastric haemorrhage.
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