Peripheral blood leucocytes ornithine decarboxylase activity in chronic myeloid leukemia patients: prognostic and therapeutic implications
Introduction
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent hematopoitic stem cell with a specific cytogenetic abnormality, the Philadelphia (Ph) chromosome [1]. This chromosome results from balanced reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in the bcr–abl chimeric gene that expresses an abnormal fusion protein with tyrosine kinase activity [2]. The median age of presentation in CML is early 50s but all age groups are at risk. Its course is characterized by a chronic phase (CML-CP) of a median duration of 3–5 years on treatment with conventional drugs followed by an accelerated phase (CML-AP). Accelerated phase finally transforms into blast phase in 3–6 months. Some patients (23%) of CML-CP directly convert into blast crisis without going in accelerated phase. The survival of patients with CML appears to depend on several intrinsic host factors and tumor attributes, which are not affected by conventional chemotherapeutic agents.
Future progress in the management of CML is dependent to a significant extent on our ability to distinguish between patients who have long survival from those who would develop accelerated phase early in the course of the disease. Several clinical, hematologic and cytogenetic parameters have been associated with a poor prognosis in CML [3]. The absence of Philadelphia chromosome is a major poor prognostic factor. Other factors consistently associated with poor prognosis include splenomegaly, anemia, basophilia, thrombocytosis, thrombocytopenia and a high proportion of blasts in the peripheral blood or bone marrow [4].
Ornithine decarboxlyase is the key regulator of the biosynthesis of polyamines, which are essential for cell proliferation [5]. Expression of ODC enzyme is transiently increased upon stimulation by growth factors [6], but becomes constitutively activated during cell transformation induced by carcinogen [7], viruses [8] and oncogenes [9]. Aberrant expression of ODC is not just a coincident, pleiotypic response to transformation but a critical factor contributing to oncogenesis [10]. Positioning of ODC at the convergence point of the signaling pathway of many oncogenes suggests that ODC might be transducing their transforming activity.
Ornithine decarboxlyase activity has been shown to have value as prognostic or diagnosis marker in number of cancers including colorectal cancer [11], breast cancer [12], esophageal cancer [13], prostrate cancer [14], gastric cancer [15] and familial adenomatous polyposis [16]. ODC activity has also been used as tumor sensitivity marker for chemotherapeutic agents [17]. ODC activity reflects the intrinsic proliferative behavior of the neoplastic cells. This attribute of ODC activity can make it suitable prognostic marker to study in patients with CML, which has a heterogeneous presentation and course.
We measured ODC activity in whole peripheral blood leukocytes of CML patients both chronic phase and accelerated phase and also in sex and age matched control subjects with an aim to examine the role of ODC activity in prognostic evaluation of CML patients.
Section snippets
Materials and methods
Fifty-four patients were diagnosed as chronic myeloid leukemia. Nine patients were in blast phase (medullary or extramedullary) at presentation and consequently excluded from the study. Exclusion criteria were more than 20% blast in patient’s blood or bone marrow or biopsy proved extramedullary blast disease [18]. The remaining 45 patients were the subject of present study. Inclusion criteria were (1) clinical and hematological manifestation of CML, (2) Philadelphia chromosome positive and (3)
Statistics
Comparisons of ODC activity in different groups were made using unpaired Student’s t-test. The best cut-off for ODC activity was determined by using logistic regression. Sensitivity was defined as number of patients with elevated ODC activity that converted to accelerated phase, divided by patients with ODC activity more than cut-off value. Specificity was defined as number of CML patients with non-elevated ODC activity (less than cut-off value), divided by total number of CML patients.
Result
The ornithine decarboxylase activity was measured in 45 consecutive patients of chronic myeloid leukemia (CML), 39 of whom were in chronic phase (CML-CP) and 6 patients were in accelerated phase (CML-AP) at the time of initial diagnosis. Ornithine decarboxylase activity was also measured in 15 sex and age matched control subjects. The mean ODC activity in CML-CP and CML-AP patients were 41.02±25.57 (median 39.65, range 3.54–121.39) and 67.71±44.42 (median 71.65, range 28.48–129.09) nmol/h per 10
Discussion
Clinico-hematological prognostic factors in CML tell about aggressiveness of the disease at the time of diagnosis [21]. These parameters change with treatment and do not allow us to understand the intrinsic behavior of the disease. This necessitates the search for new putative biochemical and molecular markers, which do not change with treatment with conventional chemotherapeutic agents. Molecular events that occur during transformation are better recognized and are focus of current research.
Acknowledgements
This work is supported by a research grant from UPCST, Lucknow, India. A.K. Tripathi, B.L. Tekwani and R. Chaturvedi contributed to the conception and design. A.K. Tripathi, K.K. Sawlani and R. Chaturvedi contributed to the analysis and interpretation of data. A.K. Tripathi, R. Chaturvedi and R. Ahmad provided help in drafting the article. R.L. Singh provided help in critical revision of the article for important intellectual content. A.K. Tripathi and B.L. Tekwani provided help in final
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