Objective
A trans retinoic acid (tRA; tretinoin) differentiation inducing therapy in acute promyelocytic leukaemia (APL) produces complete clinical remissions (CR's) in the vast majority of patients.
However, molecular remission of the disease, as examined by polymerase chain reaction (PCR) for the chimeric PML/RARa gene resulting from the typical APL translocation t(l5;17), are never achieved by tRA monotherapy. The induced CR's are usually short, unless chemotherapy is added. Therefore, improving the efficacy of the induced differentiation is warranted.
Based on some reports of the potential additive effect of combinations of tRA with certain differentiation inducing cytokines, we propose a study that would search for additive or synergistic differentiation inducing effects of tRA (or some other retinoids) and the appropriate cytokine. According to some reports, the candidate cytokines will be the granulocyte colony stimulating factor (G-CSF), and the interferons (IFN's) alpha and gamma. A large series of other cytokines will be screened for potentiation of the effect of retinoids as well.
The differentiation inducing effects of the retinoids and cytokines will be studied in our myeloid leukaemia cell line model ML-l (a non-APL myeloid cell line), and they will be compared to the effects in a "true" APL cell line, NB4. Primocultures from APL patients will be included in the study as well.
We propose that the markers of terminal granulocytic monocytic differentiation, such as the nuclear segmentation (in the granulocytic series), chromatin condensation, lack of active nucleoli and lack of cell multiplication should be examined.
Functional and immunophenotyping studies will be performed in parallel. In addition, PCR analyses of the PML/RARa gene will be done. These molecular studies will be also performed to help in the differential diagnosis of APL (in some instances, the molecular study is the only method to prove APL) and for monitoring minimal residual disease in APL patients treated in Prague.
Taken together, the scientific goal of the proposal is to find the optimal combinations of retinoids and cytokines, that might eventually be advocated into a clinical trial.
The more practical goal is to introduce the PCR techniques of proving the PML/RARa gene into clinical usage in the Czech Republic.
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Coordinator
06122 Perugia
Italy
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