Biomedical subjects
Publications and source records attributed to H D Preisler.
Fifteen patients with myelodysplastic/myeloproliferative disorders were treated with high-dose cytosine arabinoside therapy. While severe toxicity was produced in every patient, only two of the 15 patients entered complete remission and two achieved partial remission status. The therapeutic responses were confined to patients who had severe myelofibrosis of apparently recent onset.
In order to establish a method for studying myeloid differentiation, light density, non-adherent, T-cell depleted mononuclear cells prepared from 26 normal peripheral blood buffy-coats were cultured in McCoy'5A medium supplemented with 15 per cent fetal calf serum (FCS) for three weeks at 37 degrees C in a humidified 5 per cent CO2 atmosphere. The total number of viable cells in the cultures on weeks 1 and 2 represented 73 +/- 10 per cent and 98 +/- 41 per cent of the initial number of viable cells seeded. After one week, blasts represented 26 +/- 10 per cent of the initial number of viable cells while all the initially contaminating mature granulocytes had disappeared. After two weeks, granulocytic differentiation was noted in most cultures and viable myelocytes and more mature cells represented 45 +/- 26 per cent of the initial number of viable cells. The differentiation was independent on the lot of FCS used. The addition of PHA stimulated leukocyte conditioned medium to the cultures did not enhance granulocytic differentiation. The granulocytic differentiation observed in the absence of exogenous CSF persisted after removing the cells adhering to the bottom of the flasks on day 2 of the culture. An endogenous colony stimulating activity was detected in the cultures on week 3 but its intensity did not clearly correlate with the degree of granulocytic differentiation.
High-dose cytosine arabinoside therapy was administered to 29 patients with poor-prognosis acute nonlymphocytic leukemia. In an attempt to reduce toxicity, therapy was divided into an initial 4-day course of therapy, followed by a 3-day course of the marrow aspirate examined 1 week after the end of treatment contained substantial numbers of leukemic cells. Of the 29 patients, 5 entered complete remission, 2 of them after the initial 4-day course of therapy. The toxicity of split-course therapy was the same as that of conventional 6-day high-dose cytosine arabinoside therapy. This study demonstrates that the modification of high-dose cytosine arabinoside therapy used in this study failed to reduce toxicity and produced a lower remission rate than that obtained with the 6-day course of therapy.
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Two hundred patients with acute nonlymphocytic leukaemia received remission induction therapy consisting of cytosine arabinoside and an anthracycline antibiotic. Analysis of the pretherapy characteristics of the patients demonstrated that patient age was the most important factor in determining whether or not the patient would survive remission induction therapy. Assessment of the characteristics of the bone marrow after 6 d of therapy permitted the recognition of patients who were likely to fail to enter remission because of persistent leukaemia. Taken together, these observations demonstrate that it is possible to identify patients for whom conventional chemotherapy is not likely to be of benefit either because it is too intensive or because it is not intensive enough to produce a complete remission.
Given the time and effort expended by investigators and given the large numbers of patients studied, there are disappointingly few "predictors" of response. From the clinical perspective, aside from performance status, age, prior history of toxic exposure, and grossly abnormal organ function, there are essentially no reliable indicators of the likelihood of a patient surviving remission induction therapy. The absence of such indicators might reflect the fact that without grossly abnormal organ function, all patients generally begin with an equal possibility of survival and that events which occur during therapy determine survival. One thing is certain, death directly attributable to leukemic cell overgrowth despite chemotherapy is an extremely rare event. Hence, therapeutic inadequacy in this sense, at the time of initial diagnosis, is not a common cause of treatment failure. Studies aimed at the prediction of leukemic cell responsiveness to therapy have been plagued by two general problems. The first is that the drug sensitivity assays have been quite primitive. For example, the ability of a cell to take up a drug is not synonymous with sensitivity to that drug. Additionally, tests which are dependent upon assays capable of making measurements in only a small subpopulation of cells, such as in vitro clonogenic assays, are likely to have only limited applicability. On the other hand, assays which measure the properties of the leukemic cell population as a whole are incapable of recognizing arabinoside therapy have provided data which suggest that in addition to patient survival three conditions must be satisfied if a complete remission is to occur: the pretherapy leukemic cell mass must be moderate or low, an adequate number of cells must be synthesizing DNA, and cytosine arabinoside must produce significant inhibition of DNA synthesis in vitro. Each factor is consistent with what is known about cytosine arabinoside: it is an S-phase-specific agent which must be incorporated into DNA in order to kill leukemic cells. When the relationship between these same factors and response to combination chemotherapy were studied, not unexpectedly, no relationship was discerned. Finally, in this setting pharmacokinetic studies have demonstrated that the amount of araCTP formed in leukemic cells in vivo when doses of 2 g and 3 g/m2 are administered are indistinguishable, thereby explaining the clinical equivalence of these two dosage levels.(ABSTRACT TRUNCATED AT 400 WORDS)
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Patients with acute myelogenous leukemia in relapse who were ineligible for further anthracycline therapy either because they were judged to be anthracycline resistant or had received the maximum doses were randomized to receive high-dose cytarabine (3 g/m2 every 12 hours for 6 days) or amsacrine (75 mg/m2 daily for 7 days). The response rates in both groups were similar: three of 25 patients given high-dose cytarabine and three of 23 given amsacrine obtained complete remissions.
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Near-tetraploid cell populations were observed in a case of T-cell acute lymphoblastic leukemia (T-ALL) and in one of acute myeloblastic leukemia (AML). In the ALL case, hyperdiploid chromosomal changes, characterized by an isochromosome 17q [i(17q)], as well as other changes, were seen at the onset of the disease. At the first relapse, hypertetraploid cells appeared in about 10% of the mitoses in the bone marrow (BM), and by the second and third relapses, the hypertetraploidy was present in more than 90% of the mitoses in the BM. Even though karyotypic instability was evident, all abnormal karyotypes contained one or two i(17q) at every sampling. In spite of karyotypic instability at each relapse, karyotypic evolution was observed whenever relapse occurred. A normal female karyotype was confirmed in the BM of each period. Immunologic examinations performed at each sampling revealed no recognizable changes before and after the appearance of tetraploidy. In the AML case, which was classified as FAB M2, cytogenetic examination was performed at diagnosis and relapse. In both, hypotetraploid cells were observed in over 60% of the BM cells; the modal chromosome number was 90. Banding analysis was successful at relapse, and a pseudodiploid clone characterized by t(8;21) and a hypotetraploid clone with two t(8;21) and a loss of two Y chromosomes were observed in the same BM sample. A normal male karyotype was also observed in BM cells. In both cases, giant and bizarre blasts were seen in the BM. A close correlation between near-tetraploid mitoses and giant and bizarre blast cells in BM smears of the same samples was observed. Previously published tetraploid acute leukemia cases analyzed with banding methods were accumulated and compared with our two cases.
Twenty-three patients with chronic-phase CML have been treated with intermittent courses of busulfan to determine if the duration of unmaintained remission becomes progressively shorter with successive courses of therapy and to determine whether there was a relationship between cluster and colony formation, suicide index of CFUc, labeling index, percentage of cells in S-phase (as determined by cytofluorographic DNA histogram analysis), in vitro sensitivity of the CFUc to busulfan, and response to busulfan therapy. Serial studies in individual patients and the group as a whole revealed no relationship between changes in the cellular parameters described above and response to busulfan. The white blood cell (WBC) doubling time with serial courses of busulfan in individual patients did not always progressively decrease as has been previously reported. In vitro studies of CFUc in chronic-phase CML appear to be of no value in predicting response to busulfan.
A 17-year-old white male with a past history of chronic inhalational abuse of plastic glue was referred to our institution for sore throat, cervical adenopathy, and an abnormal peripheral blood smear. A diagnosis of acute myelomonocytic leukemia was made and abnormalities in cytogenetic studies were demonstrated. Specific inquiry regarding this form of drug exposure should be pursued when searching for possible etiologies of malignant disease.
A method has been developed to improve the quality of autoradiography. In addition to using high specific activity thymidine (3HTdr), low temperature exposure and scintillation fluid, FdUR was added to the cell suspension during incubation. It led to an increased amount of 3HTdr incorporation by the cells. By this method, the grain density over positive cells was increased and the background was minimal.
A rapid and convenient method for estimating S-phase cells in a population was developed which detects bromodeoxyuridine (BrdU) incorporation into DNA by means of monoclonal anti-BrdU antibodies. This immunofluorescence technique (RPMB technique) was compared to autoradiographic (ARG) detection of tritiated thymidine (3HTdr) grains incorporated into the DNA. Using incubation periods for BrdU and 3HTdr ranging from one minute to one hour and detecting their incorporation by ARG and RPMB techniques, it became apparent that the RPMB technique was far more sensitive than ARG in addition to being extremely easy to perform. Some possible utilities of the RPMB technique are discussed.
The reliability of DNA histogram analysis in accurately estimating S-phase cells from human tumors was tested by comparing the results to those of simultaneously obtained tritiated thymidine labeling index (LI) studies. Patients with chronic myelocytic leukemia (CML) during chronic phase were selected for study because the Philadelphia chromosome (Ph) was the only cytogenetic abnormality in each case and, since it is a balanced translocation, the frequently encountered problem of aneuploidy in human neoplastic cells was avoided. Unfortunately, when 30 CML patients were studied simultaneously by DNA histogram analysis and LI studies, the correlation coefficient between the two results was only r = 0.611. A comparison of three different mathematical programs for DNA histogram analysis showed that none was completely satisfactory. We conclude that DNA histogram analysis does not provide the same data as autoradiographically processed labeling index studies even in patients with Ph-positive CML during the chronic phase when the situation is not complicated by additional aneuploidy.
A monoclonal antibody against bromodeoxyuridine (BrdUrd) was produced, and a rapid slide technique (RPMB technique) was developed for the estimation of S-phase cells in a population using this antibody. Bone marrow cells from patients with acute nonlymphocytic leukemia (ANLL) were studied by both the RPMB technique and tritiated thymidine (3HdThd) labeling index studies. The percentage of S-phase cells obtained by each method was compared in 50 samples, and the correlation coefficient was r = 0.89. A "double label" method is also described in which cells were simultaneously incubated with either BrdUrd and 3HdThd or BrdUrd and tritiated cytosine arabinoside (3HAra-C). The samples were first processed by the RPMB technique and then by autoradiography. Results showed only black grains overlying the nuclei of fluorescent cells in each group. An automated microphotometer was used to quantitate grains and fluorescence from each cell. This demonstrated an almost direct relationship between grains and fluorescence from BrdUrd + 3HdThd slides, whereas different patterns of relationship were noted from BrdU + 3HAra-C slides of leukemic patients. Their implications are discussed in the text. Finally, intravenous infusions of BrdUrd was given to five leukemic patients. S-phase cells were recognized distinctly within 5 min of starting the infusion. The percentage of S-phase cells was almost identical from in vivo and in vitro samples. Various possibilities of studying the biological behavior of acute leukemias and analyzing cell cycle characteristics are discussed.
HL-60 cells were exposed to tritiated thymidine (3HTdR) alone (control group), to cytosine arabinoside followed by 3HTdR or to tritium labelled cytosine arabinoside (3H-AraC) for one hour followed by incubation with colcemide to arrest them during metaphase. Autoradiographic slides were prepared and cell counts were at 1, 24, 48 and 72 h. The studies demonstrated that HL-60 cells exposed to high concentrations of AraC (10 micrograms ml-1) can pass through the S-phase as the G2-phase of the cell cycle and enter mitosis. Despite completing the S-phase, the cells exposed to AraC were severely damaged and had already begun to die.