Biomedical subjects

D Spriggs

Publications and source records attributed to D Spriggs.

65 records · Page 4Linked to original sources

PubMed1987

Induction of tumor necrosis factor expression and resistance in a human breast tumor cell line.

Tumor necrosis factor (TNF) is a polypeptide cytokine that is cytotoxic to some but not all tumor cells. The basis for resistance to the cytotoxic effects of this agent remains unclear. We have studied the development of TNF resistance in human ZR-75-1 breast carcinoma cells. ZR-75-1 cells have undetectable levels of TNF RNA and protein. However, TNF transcripts are transiently induced in these cells by exposure to recombinant human TNF. This induction of TNF RNA is associated with production of TNF-like protein in cell lysates and culture supernatants. Stable resistance to TNF-induced cytotoxicity develops when ZR-75-1 cells are exposed to increased concentrations of TNF. The TNF-resistant cells, designated ZR-75-1R, continuously express TNF transcripts and a TNF-like protein. Furthermore, ZR-75-1R cell supernatants contain cytotoxic activity that is abrogated by polyclonal antibody against TNF. The ZR-75-1R cells also possess TNF receptors that are occupied or down-regulated by the TNF-like protein. These findings thus suggest that (i) TNF induces TNF transcripts and production of a TNF-like protein in ZR-75-1 cells and (ii) resistance to TNF-induced cytotoxicity is associated with stable TNF expression.

Breast Neoplasms↗

PubMed1986

Incorporation of 9-beta-D-arabinofuranosyl-2-fluoroadenine into HL-60 cellular RNA and DNA.

The incorporation of 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) into HL-60 cellular nucleic acids was monitored by cesium sulfate gradient centrifugation. The results demonstrated that F-ara-A incorporated into both RNA and DNA. These findings are in contrast to those previously obtained with 1-beta-D-arabinofuranosylcytosine (ara-C) and 9-beta-arabinofuranosyladenine (ara-A) which demonstrated incorporation of these nucleosides only in DNA. F-ara-A inhibited HL-60 proliferation, and the incorporation of F-ara-A into both DNA and RNA correlated with loss of clonogenic survival. Furthermore, cytostatic concentrations of F-ara-A resulted in the appearance of a more mature phenotype, a finding consistent with the effects of other inhibitors of DNA synthesis. The incorporation of F-ara-A into RNA and DNA should provide new insights regarding the mechanism of action of this agent.

Carboxylesterase↗

PubMed1986

Incorporation of 5-fluorodeoxycytidine and metabolites into nucleic acids of human MCF-7 breast carcinoma cells.

Several mechanisms of action have been proposed for the antitumor agents, 5-fluorouracil (FUra) and 5-fluorodeoxyuridine (FdUrd), including their incorporation into both cellular RNA and DNA. Another fluorinated pyrimidine, 5-fluorodeoxycytidine (FdCyd), has been shown to be even more active than FdUrd against certain experimental tumors. Although FdCyd is deaminated to FdUrd, the precise mechanism of action of this agent has remained unclear. We have therefore monitored the incorporation of FdCyd and its metabolites into the nucleic acids of human MCF-7 breast carcinoma cells. The results demonstrate the internucleotide incorporation of FdCyd in MCF-7 DNA. The results also demonstrate that FUra residues are detectable in both MCF-7 DNA and RNA following treatment with FdCyd. Cytidine and deoxycytidylate deaminase inhibitors increased the extent of (FdCyd) DNA synthesis, but they had little if any effect on formation of (FUra) RNA. In contrast, deoxyuridine increased incorporation of FdCyd into DNA and blocked the formation of FUra RNA. Deoxyuridine also enhanced the cytotoxicity associated with FdCyd treatment. The present results further demonstrate that FdCyd inhibits postsynthetic methylation of MCF-7 DNA. These findings would suggest that FdCyd has multiple mechanisms of action and that incorporation of this agent into DNA distinguishes its effects from those of FUra and FdUrd.

Azacitidine↗

PubMed1985

Treatment of preleukemic syndromes with continuous intravenous infusion of low-dose cytosine arabinoside.

Preleukemic syndromes compose a group of acquired bone marrow disorders characterized by dysplastic maturation of hematopoietic cells and peripheral blood cytopenias. These syndromes have been generally considered untreatable. We administered low doses of cytosine arabinoside by continuous infusion for 14 to 21 days (20 mg/m2/d) to 16 patients with preleukemia in various stages of evolution to acute leukemia. Steady state plasma cytosine arabinoside levels ranged from 41.8 to 64.2 nmol/L. Eleven patients demonstrated marked improvement in hematopoiesis and loss of transfusion requirements for periods ranging from two to 27 + months. All but one responding patient developed recurrent pancytopenia, but additional responses to low-dose cytosine arabinoside were achieved in five of five retreated patients. Median overall survival time is 12 months for the 11 responding cases, and nine months for nonresponders. The major toxicity of low-dose cytosine arabinoside is myelosuppression, and most patients required platelet transfusion support and administration of antibiotics. Chromosome analyses demonstrated evolution to a new clone of hematopoietic cells in three patients, and persistence of the same abnormal clone in another patient. These results suggest that low-dose cytosine arabinoside therapy may result in improved hematopoiesis by promoting maturation or by selecting new stem cell clones. Low-dose cytosine arabinoside therapy thus deserves further evaluation both as a single agent and in combination with other agents in the treatment of myelodysplastic syndromes.

Adult↗

PubMed1985

Clinical pharmacology of low-dose cytosine arabinoside.

Low doses of cytosine arabinoside (ara-C) have recently been administered by intravenous (IV) infusion and intermittent subcutaneous (SC) injection to patients with pre-leukemia and acute leukemia. Our studies have demonstrated that the continuous IV infusion of low-dose (20 mg/m2/d) ara-C produces hematologic improvement in patients with preleukemic syndromes. The present work has monitored plasma ara-C levels in five of these patients. The results demonstrate mean steady-state plasma levels ranging from 1.8 to 6.9 X 10(-8) mol/L. The range for total drug exposure (area under the curve) for the 14-day course was 6.5 to 15.9 X 10(-6) mol/L X hour. These findings have been compared to the pharmacokinetics of ara-C (10 mg/m2) given by bolus SC injection. This dose schedule resulted in peak ara-C levels 15 minutes after injection that were tenfold to 30-fold higher than the mean plasma level achieved during continuous IV infusion in the same patient. Furthermore, there was no detectable plasma ara-C at six hours after bolus injection. The differences in ara-C pharmacology for the continuous IV infusion and bolus SC injection dose schedules may contribute to the variability in response and toxicity achieved with these regimens.

Acute Disease↗

PubMed1984

Induction of terminal differentiation in human K562 erythroleukemia cells by arabinofuranosylcytosine.

We have previously demonstrated that continuous exposure of human HL-60 human promyelocytes to 1-beta-D-arabinofuranosylcytosine (ara-C) results in the induction of terminal differentiation to monocyte-like cells. The present study extends these findings by demonstrating that ara-C induces hemoglobin synthesis in human K562 erythroleukemia cells. This effect occurs maximally at an ara-C concentration (5 X 10(-7) M) that results in K562 cytostasis. In contrast to the reversible effects of hemin and hydroxyurea on globin synthesis in this cell line, we have found that the induction of K562 hemoglobin synthesis by ara-C is irreversible. An induction of K562 hemoglobin synthesis also occurs with aphidicolin, another inhibitor of S-phase DNA synthesis, but not with vinblastine, an inhibitor of mitosis. Finally, ara-C induction of a differentiated K562 phenotype is accompanied by the loss of self-renewal capacity, a finding consistent with terminal differentiation.

Cell Differentiation↗

PubMed1984

Effects of 1-beta-D-arabinofuranosylcytosine incorporation on eukaryotic DNA template function.

1-beta-D-Arabinofuranosylcytosine (ara-C) incorporates into DNA, and the extent of this incorporation correlates significantly with inhibition of DNA synthesis. The incorporated ara-C residue provides a poor primer terminus for further chain elongation. There is a highly significant relationship between formation of (ara-C) DNA and loss of clonogenic survival. The present studies confirm that incorporation of ara-C into DNA, and not the competitive inhibition of DNA polymerase, is responsible for inducing lethal cellular events. The results also demonstrate that the incorporated ara-C residue is not excised from the DNA strand. Furthermore, the presistence of ara-C residues in DNA inhibits recovery of DNA synthesis following exposure to drug. The relative DNA chain-terminating effect of ara-C provides several mechanisms of action that explain internucleotide and chain terminus positioning of ara-C residues, reinitiation of previously replicated DNA segments, and DNA strand or chromosomal breaks. The precise mechanism of action is dependent upon dose scheduling of this drug.

Animals↗

PubMed1984

Relationships among Ara-CTP pools, formation of (Ara-C)DNA, and cytotoxicity of human leukemic cells.

Cytosine arabinoside (Ara-C) is the most effective agent in the treatment of acute myelogenous leukemia. This agent incorporates in leukemic cell DNA, and the extent of this incorporation correlates with loss of clonogenic survival. The incorporated Ara-C residue behaves as a relative DNA chain terminator, and the extent of (Ara-C)DNA formation correlates with inhibition of DNA synthesis. The incorporation of Ara-C into DNA requires the formation of Ara-CTP, and previous measurements of this metabolite have also been correlated with cytotoxicity. Because it is clinically relevant to define biochemical parameters predictive of Ara-C cytotoxicity, the present studies were undertaken to determine the relationship among Ara-CTP pools, formation of (Ara-C)DNA, and loss of clonogenic survival. The results demonstrate that the incorporation of Ara-C into DNA is the single most powerful predictor of cell lethality. Furthermore, although there is a correlation between Ara-CTP pools or continuous cellular exposure to Ara-CTP and cell kill, these relationships are less significant than that obtained with formation of (Ara-C)DNA. The extent of Ara-C incorporation into DNA can be predicted by the product of the Ara-CTP level and time (T), thus supporting the concept that Ara-C incorporation is dependent on continuous exposure to the triphosphate metabolite. These findings support the formation of (Ara-C)DNA as a highly predictive parameter of lethal cellular events.

Arabinofuranosylcytosine Triphosphate↗

PubMedDate not supplied

Streptococcus agalactiae (group B) endocarditis--a description of twelve cases and review of the literature.

The group B streptococcus has been shown to be a major cause of meningitis in the newborn and an occasional cause of endocarditis and sepsis in postpartum women. Little attention has been devoted to this organism as a cause of bacterial endocarditis. Twelve patients with group B streptococcal endocarditis were seen at The Presbyterian Hospital, New York, NY, between 1974 and 1985. There were seven women, five men. Ages ranged from 32 to 81 years. Serious underlying disease was present in all - diabetes mellitus in seven, carcinoma in three (bladder in two, and breast in one), alcoholism in three, malnutrition in two, heroin addiction in one, tuberculosis in one, serious prior valvular heart disease in two. The aortic valve was affected in four patients - mitral in two, mitral and aortic in one, tricuspid in four, unknown in one. The presentation was acute in seven patients. Metastatic infection occurred in seven, heart failure in six, major emboli in four, septic pericarditis in one, myocardial abscess in one. The group B streptococcus should be considered as a pathogen capable of causing acute endocarditis in certain patients with defects of host defense, particularly patients with diabetes mellitus, carcinoma or alcoholism. Cardiac surgery may be necessary in these patients due to the rapid destruction of the valves which occurs, in spite of the fact that the organisms are usually highly susceptible to penicillin.

Adult↗

PubMedDate not supplied

A concomitant ATP-depleting strategy markedly enhances anticancer agent activity.

Most anticancer agents effect DNA damage which initiate the cell death pathways of necrosis and apoptosis, but cancer cells of lesser sensitivity are only sublethally injured, and recover. The two death pathways and their interelationships in the presence of endogenous inhibitors of apoptosis and genetic deletions that facilitates only sublethal damage, are reviewed. Both ATP and pyrimidine levels in the sublethally injured cancer cells are reduced but not to low levels insuffient to sustain cell viability. However, this sublethal damage by the anticancer agent creates a therapeutic opportunity for further reduction of these key metabolites to lower levels that will not support life. Data in tumor-bearing animals is reviewed demonstrating that a combination of ATP-depleting agents plus a de novo pyrimidine inhibitor (PALA) administered concomitantly with each of nine different anticancer agents markedly enhances tumor regression rates,and even produces some cures. It is necessary to deplete tumor ATP levels seveerely (>85%) by a combination of agents that block both synthesis (6-methylmercaptopurine riboside, a purine de novo synthesis inhibitor) and generation of ATP(6-aminonicotinamide, an inhibitor of glycolysis.) Cell viability cannot be sustained if the intracellular ATP level is reduced to 15% of normal or below. In vivo data employing this novel therapeutic strategy with cisplatin is presented. The potential significance of these findings to the improvement of cancer treatment is discussed.

Adenosine Triphosphate↗

PubMedDate not supplied

Rationale and clinical status of 41.8 degrees C systemic hyperthermia tumor necrosis factor, and melphalan for neoplastic disease.

Dramatic clinical results have been obtained in malignant melanoma and sarcoma using hyperthermic limb perfusion in combination with tumor necrosis factor (TNF) and melphalan (L-PAM). In order to extrapolate these results to systemic treatment, a preclinical research program was initiated to study the interactions of hyperthermia, TNF, and L-PAM. Based on these results, a Phase I clinical trial of whole body hyperthermia (WBH) and L-PAM was initiated and completed. Clinical results obtained were consistent with initiating two second generation studies: a) a Phase II study of WBH and L-PAM for malignant melanoma; b) a Phase I study of WBH, TNF and L-PAM. Both of these studies are currently active at the University of Wisconsin Comprehensive Cancer Center. The following review summarizes the laboratory and clinical data obtained to date regarding this systemic multi-modality treatment approach.

Antineoplastic Agents, Alkylating↗