Poor prognosis acute myelogenous leukemia: 3—biological and molecular biological changes during remission induction therapy
Introduction
The outcome of remission induction therapy in acute myelogenous leukemia (AML) is determined by, (1) the direct effects of the therapy on the leukemia cells; (2) the behavior of the leukemia cells which survive remission induction therapy; and (3) the ability of the patient to survive the side effects of chemotherapy. Earlier studies by our group demonstrated that significant regrowth of the leukemia cells which survive cytotoxic therapy can result in remission induction failure [1]. This type of resistance has been named ‘regrowth resistance’ and is commonly encountered during the treatment of poor prognosis AML, CML, lymphomas, and solid tumors [2]. The same phenomenon reduces the efficacy of courses of remission consolidation chemotherapy administered to patients with standard prognosis AML resulting in short remissions [3].
The studies described here were designed to assess the behavior of leukemia cells which survived chemotherapy so that the mechanisms responsible for regrowth resistance could be identified. To accomplish this goal bone marrow cells were studied before and 3 days after a single day of chemotherapy was administered. These studies describe the direct effects of chemotherapy on AML cells and in its indirect effects on cytokine transcript levels in the leukemia cells. The percent S phase cells and telomerase activity were also measured.
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Patients who participated in the study
To participate in this study a patient had to have a diagnosis of AML and one or more of the following, age 70 years or greater, a history of MDS or MPD prior to the development of AML, and/or a history of toxic exposure. Twenty-five patients were registered onto this study after informed consent was obtained but 24 were treated [4]. Patient ages ranged from 23 to 80 years with 48% of patients being 70 or older. Eleven of the patients who were treated were females and 13 were male. Eighteen
Effects of cytotoxic therapy on the wbc count and on the leukemic cells in the marrow
The administration of two doses of cytarabine and a single dose of mitoxantrone had a profound effect on both the white blood cell count and on the bone marrow. The wbc count fell from 25.4±8.7×103/μl (7.1) to 1.5±0.36×103/μl (1, P<0.001). The mutational status of the p53 gene influenced the effect of chemotherapy on the wbc. For leukemias with wt p53 genes the wbc fell by 25.6±17.6×103/μl (−12.6) while for leukemias with mutant p53 genes the wbc count rose by 7.8±3.6×103/μl (3.6, P=0.002).
The
Discussion
Regrowth resistance is a significant contributor to treatment failure in poor prognosis AML [1], [2]. The biological basis of this phenomenon has been difficult to define when standard remission induction regimens are administered since few leukemia cells can be obtained for study after intensive chemotherapy. In contrast the remission induction regimen described here utilizes 2 one day pulses of chemotherapy administered 96 h apart. The 96 h separation permits the acquisition of cells prior to
Acknowledgements
This work is supported by the National Institute of Health/National Cancer Institute 1 P0-1 CA75606-04 and by a contribution from the Alza Corporation. E. Devemy and B. Li developed the concept, design, analysis of the data, drafting the paper and gave final approval. M. Tao, E. Horvath and H. Chopra assisted with data analysis and gave final approval. L. Fisher assembled the data and gave final approval. J. Nayini provided study materials, technical support and gave final approval. S. Creech
References (22)
- et al.
Poor prognosis acute myelogenous leukemia: 1-Response to treatment with high dose cyarabine/mitoxantrone/ethyol (Amifostine)
Leuk. Res.
(2000) - et al.
Poor prognosis acute myelogenous leukemia: 2-Biological and molecular biological characteristics and treatment outcome
Leuk. Res.
(2000) - et al.
Differences in cell cycle characteristics amongst patients with acute nonlymphocytic leukemia
Blood
(1987) - et al.
Apoptosis in bone marrow biopsies involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes
Blood
(1995) - et al.
Cytokine gene activity in AML cells in vivo in patients
Leuk. Res.
(1998) - et al.
Mutations in N-ras predominate in acute myeloid leukemia
Blood
(1987) - et al.
IL1α expression and treatment outcome in acute myelogenous leukemia (AML)
Blood
(1991) - et al.
Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor ***1 and cancer chemotherapy compounded in myeloid leukemic cells
Blood
(1992) - et al.
Some reasons for the lack of progress in the treatment of acute myelogenous leukemia
Leuk. Res.
(1992) - et al.
Regrowth resistance as a likely significant contributor to treatment failure in drug sensitive neoplastic diseases
Cancer Invest.
(1997)
The relationship between tumor proliferation and the response of malignant disease to cytotoxic therapy: Some lessons learned from cell cycle studies
Cancer Res. Ther. Control
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