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Research Article Free access | 10.1172/JCI105553
Division of Clinical Chemotherapy, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
Division of Biophysics, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
Department of Medicine, Memorial and James Ewing Hospitals for Cancer and Allied Diseases and Cornell University Medical College, New York, N. Y.
†Address requests for reprints to Dr. Bayard Clarkson, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
‡Supported by U. S. Public Health Service graduate training grant 5T4 CA5015 from the National Cancer Institute.
*Submitted for publication February 8, 1966; accepted December 9, 1966.
This investigation was supported in part by research grants CA-03215, CA-05826, and CA-08748 from the National Cancer Institute, U. S. Public Health Service.
Presented in part at the Fifty-seventh Annual Meeting of the American Society for Clinical Investigation, Atlantic City, N. J., May 1965.
Find articles by Clarkson, B. in: JCI | PubMed | Google Scholar
Division of Clinical Chemotherapy, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
Division of Biophysics, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
Department of Medicine, Memorial and James Ewing Hospitals for Cancer and Allied Diseases and Cornell University Medical College, New York, N. Y.
†Address requests for reprints to Dr. Bayard Clarkson, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
‡Supported by U. S. Public Health Service graduate training grant 5T4 CA5015 from the National Cancer Institute.
*Submitted for publication February 8, 1966; accepted December 9, 1966.
This investigation was supported in part by research grants CA-03215, CA-05826, and CA-08748 from the National Cancer Institute, U. S. Public Health Service.
Presented in part at the Fifty-seventh Annual Meeting of the American Society for Clinical Investigation, Atlantic City, N. J., May 1965.
Find articles by Ohkita, T. in: JCI | PubMed | Google Scholar
Division of Clinical Chemotherapy, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
Division of Biophysics, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
Department of Medicine, Memorial and James Ewing Hospitals for Cancer and Allied Diseases and Cornell University Medical College, New York, N. Y.
†Address requests for reprints to Dr. Bayard Clarkson, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
‡Supported by U. S. Public Health Service graduate training grant 5T4 CA5015 from the National Cancer Institute.
*Submitted for publication February 8, 1966; accepted December 9, 1966.
This investigation was supported in part by research grants CA-03215, CA-05826, and CA-08748 from the National Cancer Institute, U. S. Public Health Service.
Presented in part at the Fifty-seventh Annual Meeting of the American Society for Clinical Investigation, Atlantic City, N. J., May 1965.
Find articles by Ota, K. in: JCI | PubMed | Google Scholar
Division of Clinical Chemotherapy, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
Division of Biophysics, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
Department of Medicine, Memorial and James Ewing Hospitals for Cancer and Allied Diseases and Cornell University Medical College, New York, N. Y.
†Address requests for reprints to Dr. Bayard Clarkson, Sloan-Kettering Institute for Cancer Research, New York, N. Y.
‡Supported by U. S. Public Health Service graduate training grant 5T4 CA5015 from the National Cancer Institute.
*Submitted for publication February 8, 1966; accepted December 9, 1966.
This investigation was supported in part by research grants CA-03215, CA-05826, and CA-08748 from the National Cancer Institute, U. S. Public Health Service.
Presented in part at the Fifty-seventh Annual Meeting of the American Society for Clinical Investigation, Atlantic City, N. J., May 1965.
Find articles by Fried, J. in: JCI | PubMed | Google Scholar
Published April 1, 1967 - More info
Two adults with rapidly progressive acute myeloblastic and myelomonoblastic leukemia were given single injections of tritiated thymidine, and measurements were made of the growth rates of their leukemic and normal hematopoietic cells by radioautographic methods. Although almost all leukemic blasts in both marrow and blood were metabolically active as shown by their ability to incorporate tritiated uridine and leucine in vitro, only 5.6% and 6.1% of the blasts in the marrow and even fewer in the blood incorporated tritiated thymidine. The mitotic indexes of the marrow blasts were 0.66% and 0.52%; no circulating blasts were dividing. The mean generation times of the actively proliferating blasts were estimated to be 49 and 83 hours. This cannot be equated with the doubling time of the total leukemic population as there is evidence that many blasts fail to continue dividing and die. The mean durations of the phases of the blasts' mitotic cycles were as follows: DNA synthesis (S) = 22 and 19 hours, premitosis (G2) = 3 hours, mitosis (M) = 0.47 and 0.62 hour (minimal estimates), and postmitosis (G1) = 24 and 61 hours. In both patients the maximal mean transit time of the blasts in the blood was 36 hours, and the minimal numbers of actively dividing blasts present were 1.6 and 2.6 × 109 per kg of body weight.
Estimates were also made of the rates of proliferation and maturation of the residual normal erythrocytic and granulocytic cells in these two patients. Although total production was markedly diminished because of reduction in the number of normal elements, the relatively few remaining normal cells appeared to be dividing and maturing at rates that are about the same or only slightly slower than those found in normal subjects.
We conclude that main reason leukemic blasts displace normal hematopoietic precursors in acute leukemia is that the blasts largely fail to differentiate. Many die but many others persist in the marrow and elsewhere as primitive cells and continue to proliferate. As the blasts accumulate, they gradually displace the normal hematopoietic cells, most of which continue their normal course of differentiation and leave the marrow as nondividing mature cells. It is not known why the over-all production of normal cells is not adequately increased to compensate for the anemia, granulocytopenia, and thrombocytopenia that develop, but apparently the leukemic cells somehow interfere with the proliferation or differentiation or both of normal stem cells.