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Biomedical subjects

H D Preisler

Publications and source records attributed to H D Preisler.

At least 127 records · Page 7Linked to original sources
PubMed1987

Plasma levels of daunorubicin metabolites and the outcome of ANLL therapy.

Levels of plasma daunorubicin, daunorubicinol and aglycone metabolites were measured in 47 patients 3 h after daunorubicin was administered daily for three days as part of a cytosine arabinoside/daunorubicin remission induction regimen. High-pressure liquid chromatography with fluorescence detection was used for separation and quantitation of the drug and its metabolites. A wide range of plasma levels were observed regardless of the outcome of therapy. Patients who had high levels of the drug, or daunorubicinol on day 1 of therapy tended to have high levels on days 2 and 3 of the regimen. Three hours after the third daily dose of daunorubicin was administered, patients who would not enter remission had significantly higher levels of aglycone metabolites in plasma than did patients who entered remission. These data indicate that resistance to chemotherapeutic effects of daunorubicin may be connected with metabolism of the drug, especially with enhanced metabolism to aglycones.

Acute Disease↗
PubMed1987

Differing patterns of proto-oncogene expression in immature and mature myeloid cells.

Comparisons of the level of proto-oncogene expression in neoplastic cells and in normal cells are being made to determine the role of these genes in neoplastic development. Recent papers have reported that leukemic cells differ from normal cells in having higher c-myc RNA levels. One problem in interpreting these data is that leukemic and normal cell populations differ in the proportion of immature cells present in each. The studies described here, using chronic phase chronic myelogenous leukemia (CML) cells, compared the level of proto-oncogene expression in immature and mature myeloid cells. Substantial differences in the level and pattern of expression were found with the immature cells containing higher c-myc RNA levels and the mature cells containing higher histone H3 RNA levels. c-fos RNA levels parallel the distribution of monocytes. While the c-myc RNA level in the CML cell population as a whole is similar to that in normal marrow cell populations and less than that in the bone marrow cells of patients with acute myelogenous leukemia (AML), c-myc RNA levels in subpopulations of immature chronic phase CML myeloid cells approximate that found in AML cells. Additionally, the studies described here suggest that the presence of high c-myc and c-fos RNA levels in light density immature cells may be a unique characteristic of acute myeloid leukemic cells.

Adult↗
PubMed1987

A new method for studying cell cycle characteristics in ANLL using double-labeling with BrdU and 3HTdr.

Ten patients with acute nonlymphocytic leukemia (ANLL) received bromodeoxyuridine (BrdU) at 100 mg/M2 intravenously over 1 h. BrdU is incorporated into the DNA by S-phase cells and was detected by using a monoclonal anti-BrdU antibody in the bone marrow aspirate (BM) and biopsy specimens obtained at the end of the infusion. Additionally, BM was incubated in vitro with tritiated thymidine (3HTdr) and processed by our previously described double-label method. This allowed us to measure the duration of S-phase (Ts) and total cell cycle time (Tc) of myeloblasts. Data revealed a higher number of S-phase cells from biopsies (21%) than BM (5%). The Ts ranged from 9 to 35 h and Tc ranged between 36 and 152 h in different patients. Using this method, data are available within 48 h and if shown to be clinically relevant, may be useful for prospective planning of therapy in individual patients.

Adult↗
PubMed1987

Phenylbutazone-induced myelodysplastic syndrome with Philadelphia translocation.

We present a case of a 69-year-old white male with a 3-year history of a myelodysplastic syndrome probably induced by phenylbutazone, and which developed into an overt leukemic phase. Chromosome analysis in the leukemic phase revealed the bone marrow cells to contain a Philadelphia translocation [46,XY,t(9;22)(q34;q11)]. We discuss the possible association between a prior history of exposure to hemotoxins and myelodysplastic syndromes, and the rarity of a Ph translocation in drug-induced hematologic malignancy.

Aged↗
PubMed1987

Four cases with complex Philadelphia translocations, including one with appearance de novo of a "masked" Ph.

Four cases of chronic myelogenous leukemia (CML) with complex Philadelphia (Ph) translocations are described. The first case was that of a 50-year-old woman in the chronic phase of CML. Her leukemic cells showed a complex Ph translocation involving chromosomes #9, #11, and #22 [i.e., t(9;9;22;11)(11qter----11q11::9q11----9q34:: 9p11----9pter;22qter----22q11::9q34?;11 pter----11q11::22q11----22qter)]. In addition to the complex Ph translocation, the leukemic cells contained del(10)(p13). The second case was that of a 21-year-old man whose leukemic cells contained a translocation involving chromosomes #5, #9, and #22 [i.e., t(5;22;9)(q31;q11;q34)], resulting in a "masked" Ph chromosome. The third case was that of a 37-year-old man whose leukemic cells had a complex Ph translocation involving chromosomes #8, #9, and #22 [i.e., t(8;9;22)(q13;q34;q11)]. The fourth patient was a 41-year-old woman diagnosed as having CML in myeloid blastic phase, at which time the first specimen was examined by us. This blood sample showed a karyotype of 45,XX, -9, -17, -22, +mar1, +mar2,9q+. No Ph chromosome was present. A standard Ph translocation was detected in the cells obtained from the spleen, when the patient underwent splenectomy for treatment of the blastic crisis. Subsequent specimens obtained from the blood and bone marrow showed that the leukemic cells contained three clones: 45,XX, -9, -17, -22, +mar1, +mar2,9q+/46,XX, -17, +mar1,t(9;22)(q34;q11)/46,XX,t(9;22)(q34;q11). Cells with the "masked" Ph chromosome were thought to have been derived from the clone with the standard Ph translocation. We postulate that some variant Ph translocations, including those with a "masked" Ph chromosome, may be generated by a stepwise process following the genesis of a standard Ph translocation.

Adult↗
PubMed1987

Transposition of breakpoint cluster region (3' bcr) in CML cells with variant Philadelphia translocations.

A probe derived from the 3' end of the CML breakpoint cluster region (bcr) was localized in chronic myelocytic leukemia (CML) cases with complex Philadelphia translocations, [t(8;9;22)(q13;q34;q11) and t(12;9;22)(p11;q34;q11)], and with "masked" Ph chromosomes, [t(9;5;22)(q34;q31;q11) and t(9;22)(q22;q34)], by a chromosomal in situ hybridization technique. In some cases, the 3' bcr rearrangements in the DNA were examined with Southern blot analysis. In each case, a significant accumulation of grains hybridized to the 3' bcr probe was observed at chromosomal segments derived from the long arm of a chromosome #22. In some cases, the accumulation of grains was detected on both translocated segments derived from the 22q and terminal portions of Ph chromosomes; Southern blot analysis revealed that breakage in chromosome #22 occurred within DNA sequences of the 3' bcr probe involved in the Ph translocations. In a CML cell line, K562, no accumulation of grains hybridized to the 3' bcr probe was detected, except at 22q11 of the normal chromosomes #22; Southern blot analysis of this cell line revealed that the 3' bcr sequences were missing. Thus, the data presented here suggest a complexity in the formation of "masked" Ph chromosomes.

Chromosome Banding↗
PubMed1987

Breakpoint cluster region rearrangements in chronic myelogenous leukemia with a masked Philadelphia chromosome.

Cytogenetic and molecular analyses were performed in a case of chronic myelogenous leukemia. The cytogenetic study revealed that the leukemic cells of this patient contained a three-way translocation involving chromosomes #5, #9, and #22, resulting in a masked Philadelphia chromosome; the karyotype of the leukemic cells was 46,XY,t(5;22;9)(q31;q11;q34). Southern blot analysis of leukemic cell DNA was performed using a 1.1 kb HindIII-EcoRI breakpoint cluster region (bcr) probe. The results showed that BglII digested DNA showed two abnormal bcr fragments (i.e., 5.2 kb and 2.7 kb) in contrast to the results with DNA from two patients with a standard Ph chromosome [t(9;22)(q34;q11)] who showed one normal 5.0-kb bcr fragment in addition to altered fragments of about 4.3 kb or 4.0 kb. Bam HI digests of DNA from the leukemic cells of the patient with the masked Ph chromosome showed two bands (3.3 kb and 6.5 kb), whereas, DNA from the two patients with standard Ph translocations showed only a 3.3-kb bcr fragment. The results indicate that the molecular events in a masked Ph affect the bcr locus in a manner similar to that seen in standard Ph chromosomes.

Adult↗
PubMed1987

The treatment of acute non-lymphocytic leukemia.

The treatment of acute nonlymphocytic leukemia involves a two stage approach. During the first stage, remission induction, cytotoxic drugs are administered to return hematopoiesis to normal. During the second stage, therapy is administered in an attempt to prolong the duration of remission. The clinical approaches and the problems incurred during these stages are not identical. At the time of diagnosis a decision must be made regarding whether or not the patient is likely to benefit from chemotherapy. If the answer is in the affirmative, then a decision must be made regarding the appropriate chemotherapeutic regimen. The optimal approach for the treatment of patients appears to vary depending on the age of the patient and whether or not there is a history of toxic exposure in the past. Overall remission rates vary from 40% to 85% depending upon the age of the patient and the patient's past history. Patients whose leukemia is induced into complete remission benefit from therapy administered after complete remission is attained. The optimal therapy, however, has not as yet been clearly defined. Conventional maintenance therapy appears to provide little benefit. On the other hand, the more intensive therapies are associated with substantial risk to the patient. The role of these modalities in the treatment of older patients is currently under investigation.

Humans↗
PubMed1987

Proliferative characteristics of acute nonlymphocytic leukemia in vivo.

The proliferative characteristics of myeloid leukemias were defined in vivo following intravenous bromodeoxyuridine (BrdU). Fifteen patients received a 2-hour infusion of BrdU. A monoclonal anti-BrdU antibody was used to detect the in vivo incorporation of BrdU by S-phase cells. The percentage of S-phase cells obtained from the biopsies (mean 17.3%) was significantly higher (p = 0.00001) than the percentage determined from the aspirates (7.8%). It is concluded that the true estimate of S-phase cells can only be obtained from biopsies following in vivo labeling of cells synthesizing DNA. The persistence of BrdU-labeled cells in follow-up studies can be used to recognize 'residual leukemia', and the subsequent fate of these cells can be defined in vivo.

Acute Disease↗
PubMed1987

Immunoperoxidase detection of myeloid antigens in glycolmethacrylate-embedded human bone marrow.

Different methods for fixation and exposure of antigenic determinants were tested for detection of a granulocytic differentiation antigen by the monoclonal antibody L12-2, using an indirect immunoperoxidase method on semi-thin sections of undecalcified, glycolmethacrylate-embedded human bone marrow biopsies. Fixation in Bouin's solution for 3 hr gave a more intense and more homogeneous immunological staining than fixation in absolute methanol, 4% formalin, B5, or Michel's medium, and the morphological detail was excellent. Digestion by pronase or trypsin was required. Coating the glass slides with Alcian blue prevented loss of sections from the slides during the staining procedure. Bouin fixation also made possible detection of two other differentiation antigens expressed in the granulocytic series, using the monoclonal antibodies 1G10 and R1B19. Furthermore, the same technique also permitted detection of factor VIII-RAg in the megakaryocytes, as well as recognition of cells of the erythroid series by use of polyclonal rabbit antisera.

Antibodies, Monoclonal↗
PubMed1987

High-dose cytosine arabinoside as the initial treatment of poor-risk patients with acute nonlymphocytic leukemia: a Leukemia Intergroup Study.

Sixty-seven patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) who were considered to be poor candidates for treatment with cytosine arabinoside (ara-C)/anthracycline antibiotic therapy were treated with high-dose ara-C (HDara-C) remission induction therapy. Thirty-four of the 67 patients had a hematologic disorder before developing acute leukemia or had a history of exposure to marrow toxins, 23 patients were greater than 70 years old, and 10 patients had medical problems that were felt to be a contraindication to therapy with an anthracycline antibiotic. Forty-two percent of patients entered complete remission (CR), whereas 22% failed to enter remission because of persistent leukemia. Treatment was associated with substantial toxicity varying from nausea and vomiting to irreversible cerebellar toxicity. Thirty-four percent of patients died during therapy. Poor performance status, a low serum albumin, and a low platelet count were associated with death during remission induction therapy, whereas a high pretherapy leukemic cell mass and a large number of residual leukemic cells in the marrow after six days of therapy were associated with treatment failure due to persistent leukemia.

Acute Disease↗
PubMed1987

Intensive remission consolidation therapy in the treatment of acute nonlymphocytic leukemia.

A pilot study was conducted to determine the possible efficacy and the toxicities associated with the administration of four courses of intensive consolidation chemotherapy to patients with acute nonlymphocytic leukemia in remission. All therapy was completed within 6 months. The median duration of remission was 22 months, with 45+% of patients in remission at 3 years and few relapses to date thereafter. Sixty percent of patients experienced significant side effects after each course of therapy. The therapy appeared to be particularly efficacious for patients less than 45 years of age, since 65% are alive at 3 years and there is no projection for a median duration of remission as yet. The cytogenetic characteristics of the leukemic cells, the percentage of S phase cells, and the height of the WBC count were the most important prognostic characteristics at diagnosis.

Acute Disease↗
PubMed1987

Progress toward predictive models for the outcome of treatment for acute nonlymphocytic leukemia.

A prognostic factor model for "high risk" patients (those more than 70 years old or with secondary leukemia) which involves the serum albumin and platelet count has recently been reported. This model permits the division of the "high risk" patient group into those with an 80% likelihood of surviving high-dose cytosine arabinoside therapy and those with a greater than 70% likelihood of dying.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Proto-oncogene expression in HL-60 cells exposed to ara-C.

To verify the reported differentiation/maturation-inducing effects of cytosine-beta-D-arabinofuranoside (ara-C, Sigma Chemical Corp, St Louis) on hematopoietic cells, we studied the morphologic changes and patterns of proto-oncogene expression in HL-60 cells that had been exposed to the drug. At the 1 X 10(-7) mol/L concentration of ara-C, approximately 10% of HL-60 cells became nitroblue tetrazolium (NBT) reduction test positive after four days exposure. However, no cells became nonspecific esterase-positive during the culture period. Doses less than 1 X 10(-8) mol/L had virtually no effect on maturation and proliferation of the target cells while doses greater than 1 X 10(-6) mol/L were lethal to HL-60 cells. Cells treated with 1 X 10(-7) mol/L and 1 X 10(-9) mol/L ara-C did not evidence any of the changes in c-myc, c-myb, c-fos, or c-fes that are noted when dimethyl sulfoxide (DMSO) or 12-0-tetradecanoyl phorbol 13-acetate (TPA, Sigma Chemical Corp, St Louis) are used to induce the differentiation of HL-60 cells. In both doses, temporary decreases of the S-phase specific and proliferation related histone H3 gene expression occurred. This phenomenon may be related to an increase in the tendency of these cells to spontaneously differentiate. Because of the possibility of drug inactivation during culture and because HL-60 cells have already matured to the promyelocytic stage, these kinds of experimental systems may be inadequate in in vitro models for low-dose ara-C therapy.

Cell Cycle↗
PubMed1987

Differences in cell cycle characteristics among patients with acute nonlymphocytic leukemia.

The proliferative characteristics of myeloid leukemias were defined in vivo after intravenous infusions of bromodeoxyuridine (BrdU) in 40 patients. The percentage of S-phase cells obtained from the biopsies (mean, 20%) were significantly higher (P = .00003) than those determined from the bone marrow (BM) aspirates (mean, 9%). The post-BrdU infusion BM aspirates from 40 patients were incubated with tritiated thymidine in vitro. These double-labeled slides were utilized to determine the duration of S-phase (Ts) in myeloblasts and their total cell cycle time (Tc). The Ts varied from four to 49 hours (mean, 19 hours; median, 17 hours). Similarly, there were wide variations in Tc of individual patients ranging from 16 to 292 hours (mean, 93 hours; median, 76 hours). There was no relationship between Tc and the percentage of S-phase cells, but there was a good correlation between Tc and Ts (r = .8). Patients with relapsed acute nonlymphocytic leukemia (ANLL) appeared to have a longer Ts and Tc than those studied at initial diagnosis. A subgroup of patients at either extreme of Tc were identified who demonstrated clinically documented resistance in response to multiple courses of chemotherapy. We conclude that Ts and Tc provide additional biologic information that may be valuable in understanding the variations observed in the natural history of ANLL.

Acute Disease↗