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Biomedical subjects

R Taetle

Publications and source records attributed to R Taetle.

121 records · Page 7Linked to original sources
PubMed1980

Thymidine as a chemotherapeutic agent: sensitivity of normal human marrow, peripheral blood T cells, and acute nonlymphocytic leukemia.

Normal marrow granulocyte (CFU-GM) and peripheral blood T-lymphocyte (CFU-TL) colony-forming cells were studied for their sensitivity to high concentrations of thymidine (dThd) and compared to leukemic CFU from patients with acute nonlymphocytic leukemia (ANLL). The sensitivity of two ANLL cell lines was also assessed. dThd was toxic to both CFU-GM and CFU-TL at concentrations above 10(-5) M when cultured under conditions where dThd exposure was analogous to that used in clinical trials. There was little variation in the fractional colony survival between marrow samples, and the sensitivity of CFU-GM closely approximated that of CFU-TL. Thymine was not toxic at up to 10(-3) M. In liquid culture, T cells in G0 at the start of exposure were able to proliferate in the presence of 10(-3) M dThd, whereas T cells already proliferating in response to phytohemagglutinin (PHA) at the start of dThd exposure were killed. Leukemic CFU demonstrated marked variability in dThd sensitivity; blasts from some patients were resistant to dThd, while others were greater than 100-fold more sensitive than normal CFU-GM.

Acute Disease↗
PubMed1980

Human T-cell antigens defined by monoclonal antibodies. Absence of T65 on committed myeloid and erythroid progenitors.

The complement-dependent cytotoxicity of monoclonal T-cell antibody (T101) for normal and abnormal hemopoietic progenitors was assessed. T101 demonstrated toxicity for normal T-colony-forming cells from peripheral blood and bone marrow. Cytotoxicity was absent for normal peripheral blood and bone marrow granulocytes/macrophage (CFU-C) and erythroid (BFU-E) progenitors. The antibody was also not toxic for peripheral blood blast progenitors from patients with acute myelogenous leukemia (AML). These studies indicate the absence of the antigen defined by T101 (T65) from normal progenitor cells and from blast progenitors in patients with AML. T101 may be used in the treatment of T-cell malignancies and in the prevention of graft-versus-host disease (GVHD) without damage to normal progenitor cells.

Antibodies↗
PubMed1980

Abnormal modulation of granulocyte/macrophage progenitor proliferation by prostaglandin E in chronic myeloproliferative disorders.

The effect of prostaglandin E1 (PGE1) on the in vitro proliferation of peripheral blood granulocyte/macrophage progenitors (CFUc) from the patients with chronic myeloproliferative disorders was examined. PGE1 was found to be a dose-dependent inhibitor of normal peripheral blood and bone marrow CFUc. Peripheral blood CFUc from patients with chronic myelogenous leukemia (CML) showed normal inhibition when cultured in the absence of exogenous colony stimulating factor (CSF). The addition of CSF to CML peripheral blood cultures resulted in complete abrogation of normal PGE1 inhibition. Dose-titration studies in which increasing amounts of CSF were added to CML cultures showed decreasing PGE1 inhibition with increasing CSF concentration. This observation indicated increased efficiency of competition between the colony stimulating effect of CSF and the colony inhibitory effect of PGE1 in CML. Peripheral blood CFUc from patients with myelofibrosis/myeloid metaplasia (MM) showed heterogeneous responses to PGE1 with complex dose-effect curves showing variable combinations of stimulation and inhibition of CFUc proliferation. Further studies showed that these effects of PGE1 were blocked by the prostaglandin antagonist SC-19220, and were not due to elaboration of CSF or non-CSF enhancers of CFUc proliferation from MM adherent cells. Cell fractionation studies in 2 patients, with MM showed dual populations of CFUc, one responding abnormally, and another normally to PGE1, accounting in part for the complex dose-response curves. These studies indicate that significant abnormalities exist in the in vitro response to PGE1 by CFUc from patients with chronic myeloproliferative disorders. Deficiencies in PGE 1 inhibition may contribute to the excess myelopoiesis seen in these disorders.

Cells, Cultured↗
PubMed1979

Drug-induced agranulocytosis: in vitro evidence for immune suppression of granulopoiesis and a cross-reacting lymphocyte antibody.

Two patients with agranulocytosis associated with diphenylhydantoin (DPH) therapy and clinical data suggesting suppression of granulopoiesis were investigated using in vitro culture techniques for committed granulocyte/macrophage precursors. Addition of DPH to cultures containing the patients' sera resulted in significant suppression of colony growth. Extensive studies on the acute serum from one patient revealed the drug-dependent inhibitory activity to be nondialyzable, resistant to chloroform extraction, heat stable, active in the presence of heat-inactivated fetal bovine serum, active against autologous as well as allogeneic cells, and absent from convalescent sera. Drug-dependent bone marrow colony-suppressing activity was removed by absorption on an antiimmunoglobulin-Sepharose column but not by IgG-Sepharose. The serum show non-drug dependent suppression of oxygen consumption by normal polymorphonuclear leukocytes engaged in phagocytosis and also showed evidence of ability to opsonize these cells. When the serum was incubated with mitogen-stimulated lymphocytes, suppression of 3H-thymidine uptake by autologous but not allogeneic cells was noted. Similarly, the serum suppressed short-term 3H-thymidine uptake by autologous but not allogeneic bone marrow. Absorption of the patients' sera with allogeneic polymorphonuclear leukocytes, autologous polymorphonuclear leukocytes, or autologous lymphocytes removed the drug-dependent inhibitory activity, but absorption with allogeneic lymphocytes did not. These data are most consistent with the presence of a noncomplement dependent antibody capable of suppressing granulopoiesis, mediating peripheral destruction of polymorphonuclear leukocytes, and cross-reacting with a lymphocyte antigen of limited population distribution.

Agranulocytosis↗
PubMed1978

Pulmonary histopathologic changes associated with melphalan therapy.

A case of fatal pulmonary fibrosis and atypical epithelial proliferation (AEP) in a patient with multiple myeloma treated with melphalan is presented. Review of 10 other autopsied patients with myeloma treated with melphalan but no thoracic radiation, other cytotoxic agents, or highdose oxygen therapy revealed one other patient who died with extensive pulmonary fibrosis and AEP. Four other patients with AEP not associated with pneumonitis or fibrosis were also found, while no such changes were found in 11 autopsy controls or 11 patients with myeloma who did not receive cytotoxic agents. Melphalan should be added to the growing list of agents capable of causing severe fibrotic pulmonary reactions.

Aged↗
PubMedDate not supplied

On the mechanism of toxicity of illudins: the role of glutathione.

Illudin M and illudin S, antitumor sesquiterpenes from Omphalotus illudens, have been found to react with thiols in a pH-dependent manner. The optimum pH values for reaction of illudin M with methyl thioglycolate, cysteine, and glutathione were 5.8, 5.6, and 6.1, respectively, and pseudo-first-order rate constants at 25 degrees C (10-fold excess of thiol) were 44 x 10(-3), 11.5 x 10(-3), and 11.3 x 10(-3) min-1. In all cases, thiol added to the alpha, beta-unsaturated ketone giving an unstable intermediate. Subsequent loss of the tertiary hydroxyl and opening of the cyclopropane ring afforded a stable aromatic product. The toxicity of illudin S to HL60 cells was increased by lowering glutathione levels in the cells and vice versa. General toxicity and antitumor activity of illudins are discussed in the light of these results.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Objective criteria for in-vitro responses in human tumor colony-forming assays.

The application of rigorous statistical criteria to the design and analysis of in-vitro assay techniques can lead to more reliable assessments of their utility. The authors demonstrate that an objective criterion for in-vitro drug sensitivity would yield less pronounced false-negative error rates than a fixed-cutoff rule, and would therefore be more suitable for screening of putative chemotherapeutic agents.

Colony-Forming Units Assay↗
PubMedDate not supplied

Effect of sodium thiosulfate on cis-dichlorodiammineplatinum(II) toxicity and antitumor activity in L1210 leukemia.

Concurrent administration of sodium thiosulfate reduced the toxicity of cis-dichlorodiammineplatinum(II) (DDP) in a dose-related manner in mice. Sodium thiosulfate protected mice against an otherwise lethal dose of DDP (20 mg/kg), and reduced DDP-induced weight loss. Sodium thiosulfate (800 mg/kg) injected within 1 hour before or 1/2 hour after DDP blocked nephrotoxicity as measured by a rise in BUN, an increase in kidney weight, and medullary hemorrhage. In culture, sodium thiosulfate markedly reduced the toxicity of DDP to mouse colony-forming units. Concurrent injection of sodium thiosulfate partially reduced the antitumor activity of DDP. The therapeutic dose range of DDP was expanded, but the maximum increase in lifespan of mice bearing L1210 leukemia was reduced by 40%. Sodium thiosulfate offers the possibility of systemic protection against the cytotoxicity of regionally administered DDP in man.

Animals↗
PubMedDate not supplied

Nonresponsiveness of the metastatic human lung carcinoma MV522 xenograft to conventional anticancer agents.

The human lung carcinoma cell line MV522 was previously noted to produce extensive metastasis to the lungs, spleen and lymph nodes after subcutaneous transplantation into athymic nude mice. Animals eventually succumb to these metastases, and not primary tumor growth. The ability to produce extensive metastasis after a simple subcutaneous injection in 100% of animals (> 100 tested to date) would be an advantage when screening compounds for anticancer activity. To validate the utility of this xenograft model for testing anticancer agents, we tested the ability of 10 anticancer drugs to either inhibit primary tumor growth and/or prolong life span of MV522-bearing animals. Among the 10 antitumor conventional agents, only mitomycin C and taxol demonstrated primary tumor growth inhibition. Mitomycin C produced a mild increase in median life span of 41% to 63%, while taxol had inconsistent effects. The metastatic MV522 carcinoma model appears to reflect clinical resistance of primary non-small cell lung cancer to conventional chemotherapeutic agents and should be useful for testing new anti-cancer drugs.

Animals↗
PubMedDate not supplied

In vitro and in vivo studies on the anticancer activity of dehydroilludin M.

Six first-generation illudin analogs were tested for antitumor activity using in vitro cytotoxicity and in vivo xenograft models. One analog, dehydroilludin M, inhibited xenograft growth and prolonged life span of tumor bearing animals, when administered IP or IV, whereas the parent Illudin S compound was ineffective. The efficacy of dehydroilludin M in the MV522 lung carcinoma model exceeded that of 9 known anticancer drugs, and equaled that of mitomycin C. Dehydroilludin M retained the in vitro relative selective cytotoxicity for carcinomas and myeloid leukemia cell lines noted with the parent illudin compounds. In vitro cytotoxicity data predicted response of xenografts. Dehydroilludin M also retained the in vitro activity of the parent compounds against different multidrug resistant mdr cell lines.

Analysis of Variance↗