Search PubMed⌕ Search

Biomedical subjects

J Mayes

Publications and source records attributed to J Mayes.

At least 37 records · Page 2Linked to original sources
PubMed1992

Relative activity of structural analogues of amsacrine against human leukemia cell lines containing amsacrine-sensitive or -resistant forms of topoisomerase II: use of computer simulations in new drug development.

Anilino analogues of amsacrine showed increased activity against amsacrine (AMSA)-resistant cell lines when compared with the parent compound, but the mechanisms of amsacrine resistance in these lines were unknown (Finlay, G. J., Baguley, B. C., Snow, K., and Judd, W., J. Natl. Cancer Inst., 82: 662-667, 1990). We tested the cytotoxic and DNA-cleaving activities of two amsacrine analogues which were derivatives of 9-anilinoacridine (1'-methylcarbamate and 1'-benzenesulfonamide) against an amsacrine-resistant human leukemia cell line (HL-60/AMSA) whose resistance is due to an amsacrine-resistant topoisomerase II. Neither agent could overcome the amsacrine resistance of HL-60/AMSA. Neither agent could induce HL-60/AMSA topoisomerase II-mediated cleavage of DNA in an isolated biochemical system, although at high concentrations the two analogues could inhibit HL-60/AMSA topoisomerase II-mediated DNA strand passage. Both analogues were at least as active, if not more active, than amsacrine against amsacrine-sensitive HL-60 and its topoisomerase II. Comparison of the cellular and biochemical results with those from computer simulation of the energy-minimized structures of amsacrine, its inactive isomer o-AMSA, and the two new active analogues suggests the following possibilities: (a) the positioning of the potential topoisomerase II-binding site (1'-anilino group) of the two new drugs resembles the positioning of this site in amsacrine; (b) the HL-60 topoisomerase II has a binding site which interacts with amsacrine and the two anilino analogues but not with o-AMSA, an analogue with altered positioning of the methoxy group; (c) the HL-60/AMSA topoisomerase II interacts with reduced affinity with amsacrine and the two anilino analogues, although HL-60/AMSA topoisomerase II still interacts with the structurally distinct topoisomerase II-reactive nonintercalator, etoposide; (d) because of their higher DNA binding affinity or the greater possible positions of their side groups in comparison to amsacrine, the two analogues can, at high concentrations, inhibit the strand-passing activity of HL-60/AMSA topoisomerase II.

Amsacrine↗
PubMed1991

Identification of a point mutation in the topoisomerase II gene from a human leukemia cell line containing an amsacrine-resistant form of topoisomerase II.

HL-60/AMSA is a human leukemia cell line that is 50- to 100-fold more resistant to the cytotoxic actions of the topoisomerase II-reactive intercalator amsacrine than is its drug-sensitive HL-60 parent line. Previously, we have shown that the topoisomerase II from HL-60/AMSA is also resistant to inhibition by amsacrine and other intercalating agents. We therefore sought the molecular basis for the resistance of the topoisomerase II of HL-60/AMSA and, by inference, of the HL-60/AMSA line itself. We report the cloning and sequencing of the topoisomerase II genes from both the sensitive and resistant leukemia cell lines using polymerase chain reaction technology. We have identified a single base change associated with the drug-resistant form of topoisomerase II. This mutation is present in both cloned HL-60/AMSA complementary DNA and extracted HL-60/AMSA genomic DNA. A rapid assay for this mutation in clinical samples has been developed and applied to the DNA of cells from both normal volunteers and leukemia patients. Thus far, the HL-60/AMSA genotype has not been identified in the cells from any individual, suggesting that this genotype is indeed a mutation and not an allelic form of topoisomerase II. The novel assay developed will allow a rapid search for the prevalence of this mutation in clinical samples from patients with leukemia who have relapsed following intercalator therapy.

Amino Acid Sequence↗
PubMed1991

Cross-resistance of an amsacrine-resistant human leukemia line to topoisomerase II reactive DNA intercalating agents. Evidence for two topoisomerase II directed drug actions.

HL-60/AMSA is a human leukemia cell line that is 50-100-fold more resistant than its drug-sensitive HL-60 parent line to the cytotoxic actions of the DNA intercalator amsacrine (m-AMSA). HL-60/AMSA topoisomerase II is also resistant to the inhibitory actions of m-AMSA. HL-60/AMSA cells and topoisomerase II are cross-resistant to anthracycline and ellipticine intercalators but relatively sensitive to the nonintercalating topoisomerase II reactive epipodophyllotoxin etoposide. We now demonstrate that HL-60/AMSA and its topoisomerase II are cross-resistant to the DNA intercalators mitoxantrone and amonafide, thus strongly indicating that HL-60/AMSA and its topoisomerase II are resistant to topoisomerase II reactive intercalators but not to nonintercalators. At high concentrations, mitoxantrone and amonafide were also found to inhibit their own, m-AMSA's, and etoposide's abilities to stabilize topoisomerase II-DNA complexes. This appears to be due to the ability of these concentrations of mitoxantrone and amonafide to inhibit topoisomerase II mediated DNA strand passage at a point in the topoisomerization cycle prior to the acquisition of the enzyme-DNA configuration that yields DNA cleavage and topoisomerase II-DNA cross-links. In addition, amonafide can inhibit the cytotoxic actions of m-AMSA and etoposide. Taken together, these results suggest that the cytotoxicity of m-AMSA and etoposide is initiated primarily by the stabilization of the topoisomerase II-DNA complex. Other topoisomerase II reactive drugs may inhibit the enzyme at other steps in the topoisomerization cycle, particularly at elevated concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Amsacrine↗
PubMed1991

A lack of detectable modification of topoisomerase II activity in a series of human tumor cell lines expressing only low levels of etoposide resistance.

Etoposide (VP-16) resistance is expressed following in vitro exposure of HN-1 and MCF-7 human tumor cells to the drug itself or to fractionated X irradiation. VP-16-selected sublines prove cross-resistant to Adriamycin, amsacrine and actinomycin D, whilst X-ray-pretreated sublines show cross-resistance to only actinomycin D. These differential responses, in the HN-1 series, are not associated with significant differences in amounts of immunoreactive topoisomerase (topo) II, altered topo-II catalytic activity of nuclear extracts or changes in susceptibility of the topo II to VP-16- or amsacrine-induced DNA-protein cross-link formation. Therefore significant modifications in topo II appear not to be implicated in VP-16 resistance in these HN-1 sublines.

Amsacrine↗
PubMed1991

Effect of bryostatin 1 on drug-induced, topoisomerase II-mediated DNA cleavage and topoisomerase II gene expression in human leukemia cells.

Unlike PMA, bryostatin 1 has been found to have a minimal effect on drug-induced topoisomerase II-mediated DNA cleavage and no effect on topoisomerase II mRNA levels. Furthermore, bryostatin 1 overcame the down-regulatory effects of PMA treatment on (1) drug-induced, topoisomerase II-mediated DNA cleavage, (2) drug-induced cytotoxicity, and (3) topoisomerase II gene expression. Thus, it is unlikely that the effects of phorbol ester treatment on topoisomerase II-mediated events are a direct consequence of protein kinase C activation per se. Rather, the results with bryostatin 1 suggest that the phorbol ester effects are related to more distal effects of phorbol ester treatment that may be related to monocytoid differentiation.

Bryostatins↗
PubMed1991

The effect of staurosporine on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells.

Phorbol-12-myristate 13-acetate (PMA), a stimulator of protein kinase C, dramatically decreased topoisomerase II-reactive drug-induced DNA cleavage in HL-60 human leukemia cells. The effect of staurosporine, an inhibitor of protein kinase C, on drug-induced, topoisomerase II-mediated DNA cleavage was quantified in the same cells. Staurosporine decreased the magnitude of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)- and etoposide-induced DNA cleavage in a dose- and time-dependent fashion. Measurement of several parameters of cell proliferation revealed no clear and uniform correlation between staurosporine's inhibition of these parameters and its effects on drug-induced DNA cleavage. A direct comparison with PMA's effects on drug-induced DNA cleavage showed that whereas PMA's inhibition of etoposide-induced cleavage was much greater than its inhibition of m-AMSA-induced cleavage, the magnitude of staurosporine's effect on the cleavage produced by the two topoisomerase II-reactive drugs was similar. Thus, although PMA stimulates protein kinase C and staurosporine inhibits this enzyme, it is unlikely that the actions of either on topoisomerase II-reactive, drug-induced DNA cleavage are mediated directly via protein kinase C. Furthermore, it is likely that the mechanisms by which PMA and staurosporine inhibit topoisomerase II-reactive drug-induced cleavage are different.

Alkaloids↗
PubMed1990

Phorbol ester effects on topoisomerase II activity and gene expression in HL-60 human leukemia cells with different proclivities toward monocytoid differentiation.

We examined the effects of phorbol ester treatment on topoisomerase II-mediated events in two human leukemia cell lines with different proclivities toward phorbol ester-induced monocytoid differentiation. HL-60 is the parent line that will terminally differentiate; 1E3 is a derived line that will not terminally differentiate. Within 24 h of phorbol ester treatment, etoposide-induced, topoisomerase II-mediated DNA cleavage declined 10-fold, whereas 4'-(9-acridinylamino)-methanesulfon-m-anisidide- induced DNA cleavage declined 3-fold in HL-60. In phorbol-treated 1E3, etoposide-induced DNA cleavage declined only 2-fold, whereas 4'-(9-acridinylamino)methanesulfon-m-anisidide-induced cleavage was barely affected. There was a 2- to 3-fold decline in topoisomerase II activity within the nuclear extracts from phorbol-treated HL-60 cells but not from phorbol-treated 1E3 cells. Immunoblotting experiments with anti-topoisomerase II antibodies indicated that phorbol treatment produced a structural change in the immunoreactive topiosomerase II in HL-60 nuclear extracts but produced no change in 1E3 topoisomerase II. Phorbol ester treatment also produced a decline in the level of topoisomerase II gene expression in HL-60 but not in 1E3 cells. By contrast, the cytotoxicity of etoposide in both lines was decreased following phorbol treatment. Thus, phorbols may uncouple the mechanisms linking drug-induced, topoisomerase II-DNA cleavable complex stabilization with drug-induced cytotoxicity, particularly in 1E3.

Amsacrine↗
PubMed1990

HT1080/DR4: a P-glycoprotein-negative human fibrosarcoma cell line exhibiting resistance to topoisomerase II-reactive drugs despite the presence of a drug-sensitive topoisomerase II.

HT1080/DR4 (DR4) is a doxorubicin-resistant human fibrosarcoma line that exhibits 150-fold cross-resistance to etoposide but does not overexpress P-glycoprotein (one mechanism of multiple drug resistance). We examined another possible mechanism that could explain resistance to both doxorubicin and etoposide: a quantitative or qualitative alteration in topoisomerase II, the putative nuclear target of these agents. The amount of immunoreactive topoisomerase II present in whole-cell lysates and nuclear extracts was three- to 10-fold lower in DR4 than in HT1080 cells. However, the topoisomerase II in nuclear extracts from both lines was sensitive to the effects of amsacrine (AMSA) and etoposide. Following treatment with AMSA, etoposide, and 5-iminodaunorubicin, topoisomerase II-mediated DNA cleavage in DR4 cells and nuclei was reduced compared with cleavage in HT1080 parent cells and nuclei. The difference between the HT1080 and DR4 lines in AMSA- and 5-iminodaunorubicin-induced cleavage was similar in cells and nuclei and could be due to the lower amount of DR4 topoisomerase II. By contrast, the difference between the HT1080 and DR4 lines in etoposide-induced DNA cleavage was much greater in cells than in nuclei. This finding suggested that cytosolic factors, removed from isolated nuclei, could influence the susceptibility of intact cells to the cytotoxic and DNA-cleaving actions of etoposide. The specific activities of several antioxidant enzymes, components of the cell's defense against free-radical damage that may be produced by doxorubicin or etoposide, were significantly different in HT1080 and DR4 cytosolic extracts. These differences may constitute an additional mechanism of resistance. Regardless, the magnitude of the resistance of DR4 to doxorubicin and etoposide cannot be explained solely on the basis of a topoisomerase II-related mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

A restriction fragment length polymorphism for human topoisomerase II: possible relationship to drug-resistance.

In previous studies we used Southern blotting to examine the topoisomerase II locus (on chromosome 17) in human leukemia cell lines and noted a difference in the XmnI restriction endonuclease digestion pattern between an m-AMSA-resistant line and its m-AMSA-sensitive parent line (Zwelling, L. A.; Hinds, M,; Chan, D.; Mayes, J.; Sie, K. L.; Parker, E.; Silberman, L.; Radcliffe, A.; Beran, M.; Blick, M. Characterization of an amsacrine-resistant line of human leukemia cells. Evidence for a drug-resistant form of topoisomerase II. Journal of Biological Chemistry 264:16411-16420; 1989). We now demonstrate that the variable XmnI digestion pattern represents a normal restriction fragment length polymorphism (RFLP) which is observed in subjects without malignant disease and exhibits an autosomal pattern of inheritance. These data suggest that the previously described deviation in the genomic structure of topoisomerase II in the m-AMSA-resistant cell line did not reflect a new mutation, but rather a reduction to homozygosity at the topoisomerase II locus. This reduction to homozygosity is not due to chromosomal loss, as chromosome 17-specific gene probes clearly identify two chromosome 17's in the sensitive line and four in the resistant line, using chromosome painting with a chromosome 17-specific library. Some other genetic change must be the cause of the resistance of HL-60/AMSA and its topoisomerase II to the inhibiting actions of m-AMSA.

Alleles↗
PubMed1989

Characterization of an amsacrine-resistant line of human leukemia cells. Evidence for a drug-resistant form of topoisomerase II.

HL-60/AMSA is a human leukemia cell line that is 100 times more resistant to the cytotoxic actions of the antineoplastic, topoisomerase II-reactive DNA intercalating acridine derivative amsacrine (m-AMSA) than is its parent HL-60 line. HL-60/AMSA cells are minimally resistant to etoposide, a topoisomerase II-reactive drug that does not intercalate. Previously we showed that HL-60 topoisomerase II activity in cells, nuclei, or nuclear extracts was sensitive to m-AMSA and etoposide, while HL-60/AMSA topoisomerase II was resistant to m-AMSA but sensitive to etoposide. Now we show that purified topoisomerase II from the two cell lines exhibits the same drug sensitivity or resistance as that in the nuclear extracts although the magnitude of the m-AMSA resistance of HL-60/AMSA topoisomerase II in vitro is not as great as the resistance of the intact HL-60/AMSA cells. In addition HL-60/AMSA cells are cross-resistant to topoisomerase II-reactive intercalators from the anthracycline and ellipticine families and the pattern of sensitivity or resistance to the cytotoxic actions of the various topoisomerase II-reactive drugs is paralleled by topoisomerase II-reactive drug-induced DNA cleavage and protein cross-link production in cells and the production of drug-induced, topoisomerase II-mediated DNA cleavage and protein cross-linking in isolated biochemical systems. In addition to its lowered sensitivity to intercalators, HL-60/AMSA differed from HL-60 in 1) the susceptibility of its topoisomerase II to stimulation of DNA topoisomerase II complex formation by ATP, 2) the catalytic activity of its topoisomerase II in an ionic environment chosen to reproduce the environment found within the living cell, and 3) the observed restriction enzyme pattern on a Southern blot probed with a cDNA for human topoisomerase II. These data indicate that an m-AMSA-resistant form of topoisomerase II contributes to the resistance of HL-60/AMSA to m-AMSA and to other topoisomerase II-reactive DNA intercalating agents. The drug resistance is associated with additional biochemical and molecular alterations that may be important determinants of cellular sensitivity or resistance to topoisomerase II-reactive drugs.

Adenosine Triphosphate↗
PubMed1989

A comparison of two crisis housing alternatives to psychiatric hospitalization.

This study compared outcomes for demographically matched clients four months after their admission to two short-term crisis programs. The programs provided crisis housing and case management services as alternatives to psychiatric hospitalization for clients with severe and persistent mental illness. One program met housing needs by purchasing shelter in hotels and boarding houses, and the other provided lodging in an eight-bed crisis house. In both programs, two-thirds of the clients avoided hospitalization during four-month follow-up, and both programs were effective in stabilizing clients' housing and financial situations. Clients in the purchase-of-housing program showed an increase in substance abuse problems at follow-up. Average client costs were similar in the two programs. A critical program difference was the substantially higher staff turnover in the crisis house, which was later replaced with scattered-site crisis housing.

Adult↗
PubMed1988

Effect of phorbol ester treatment on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells.

Tumor-promoting phorbol esters such as phorbol 12-myristate 13-acetate (PMA) induce the monocytoid differentiation of HL-60 human leukemia cells. The cellular receptor for PMA is protein kinase C. However, cellular events distal to protein kinase C phosphorylation are also critical steps toward differentiation. These events may include specific programs of oncogene transcription that have been associated with phorbol ester-induced leukemic cell differentiation. Recently, it has been found that topoisomerase II could be activated by protein kinase C-mediated serine phosphorylation and that PMA treatment of HL-60 cells enhanced extractable topoisomerase II from these cells. Additionally, topoisomerase II-reactive antineoplastic drugs could block PMA-induced differentiation of HL-60. This enzyme has been implicated in gene regulation, and drug-induced, topoisomerase II-mediated DNA cleavage sites have been identified within cellular oncogenes. Thus, topoisomerase II could play a critical role in the signal transduction cascade leading from PMA-protein kinase interaction to monocytoid differentiation. We have examined this relationship between topoisomerase II and PMA-induced differentiation through measurements of drug-induced, topoisomerase II-mediated DNA cleavage (via alkaline elution) in PMA-treated HL-60 cells. Etoposide-induced DNA cleavage was reduced 10-fold in HL-60 cells treated with 10 nM PMA for 24 h. Neither dimethyl sulfoxide (which produces granulocytoid differentiation) nor non-differentiation-inducing phorbol esters could produce this effect. The decreased cleavage was not due to a PMA-induced inhibition of cell-associated etoposide and was demonstrable in nuclei isolated from PMA-treated cells. The decrease was not simply related to decreased cellular proliferation rate as reflected in the inhibition of DNA synthesis because conditions leading to marked inhibition of DNA synthesis did not necessarily inhibit etoposide-induced DNA cleavage. By contrast, lower concentrations of PMA inhibited etoposide-mediated DNA cleavage disproportionately compared with PMA effects on DNA synthesis. Interestingly, PMA reduced cleavage induced by the topoisomerase II-reactive DNA intercalator 4'-(9-acridinylamino)methanesulfon-m-anisidide by 2-fold, suggesting that specific drug-DNA interactions could partially overcome the PMA-induced effect that resulted in decreased etoposide-induced, topoisomerase II-mediated DNA cleavage. Nuclear proteins in 0.35 M NaCl extracts from untreated or PMA-treated HL-60 cells were virtually identical in topoisomerase II activity and in topoisomerase II-associated drug sensitivity.(ABSTRACT TRUNCATED AT 400 WORDS)

Amsacrine↗
PubMed1988

Anion-dependent modulations of DNA topoisomerase II-mediated reactions in potassium-containing solutions.

DNA binding proteins operate in an intracellular environment of low chloride concentration, yet in vitro assays of the activities of these proteins are often performed in isotonic chloride-containing solutions. Previously, the activity of bacterial DNA-binding proteins was found to be enhanced in potassium-containing solutions in which the anion glutamate (Glu) was substituted for chloride. We have extended this observation to include eukaryotic topoisomerase I and II activities. The concentration ranges over which DNA strand passing activities of these enzymes were observed was broader in KGlu than in KCl. This was also true for the topoisomerase II-mediated DNA strand passage and antineoplastic drug-dependent DNA cleavage produced by nuclear extracts from HL-60 human leukemia cells. The rate of topoisomerase II-mediated DNA strand passage was also dependent on anion moiety and concentration in potassium-containing buffers. Drug-dependent topoisomerase II-mediated DNA cleavage in intact HL-60 cell nuclei was also anion-dependent, suggesting that anion type and concentration may influence topoisomerase II-mediated events in mammalian cells as had been described for other DNA binding proteins in prokaryotic systems. This should be considered in developing biochemical assays of topoisomerase activities to reproduce intracellular conditions.

Anions↗
PubMedDate not supplied

Presentation and management of cystic neoplasms of the pancreas.

Pancreatic cystic neoplasms are uncommon, but it is important to differentiate them from pseudocysts and ductal adenocarcinoma. A retrospective review was performed to determine distinguishing characteristics and optimal treatment. In 51 patients operated on between 1981 and 1994 at a referral center, the following cystic neoplasms were found: 20 serous cystadenomas, 10 mucinous cystadenomas, 11 mucinous cystadenocarcinomas, five cases of mucinous ductal ectasia, and five papillary cystic neoplasms. Both mucinous ductal ectasia and papillary cystic neoplasms had distinguishing features when compared to other cystic neoplasms. Mucinous ductal ectasia was seen only in men, presented with typical symptoms, and had distinctive features on endoscopic retrograde cholangiopancreatography. Papillary cystic neoplasms occurred in young women (mean age 31 years) and were larger (mean 10.3 cm). Mucinous tumors were always symptomatic, whereas 55% of serous tumors were asymptomatic (P <0.001). The overall rate of resectability was 80%, and there was one operative death (2%). Intraoperative biopsy was diagnostic in 18 (78%) of 23 cases. An actuarial 5-year survival of 52% was found for resected mucinous cystadenocarcinomas. In conclusion, papillary cystic neoplasms and mucinous ductal ectasia have distinct characteristics that differentiate them from other types of pancreatic cystic tumors. Serous cystadenoma should be considered in asymptomatic patients and these patients should be closely observed. Symptomatic neoplasms should be resected with long-term survival expected for malignant forms. (J Gastrointest Surg 1998;2:504-508.)

Adenocarcinoma, Mucinous↗
PubMedDate not supplied

Role of angiography and embolization for massive gastroduodenal hemorrhage.

The role of mesenteric angiography and embolization for massive gastroduodenal bleeding is unclear. We reviewed the records of patients who underwent angiography for acute, nonmalignant, and nonvariceal gastric or duodenal hemorrhage that was documented but not controlled by endoscopy. Fifty patients were identified over a 7-year period ending in March 1998. Only 17 patients (34%) were originally admitted to the hospital with gastrointestinal bleeding. All required treatment in the intensive care unit (mean 15 days) with a mean APACHE III score of 79 (29% predicted hospital mortality), and 32 (64%) had organ failure. A mean of 2.1 endoscopies were performed to locate the source of acute duodenal bleeding in 37 (74%) and gastric bleeding in 13 (26%). An average of 24.3 units of packed red blood cells were transfused per patient. Twenty-five patients (50%) were found to have active bleeding at angiography; all were treated by embolization as were 22 who underwent empiric embolization. Twenty-six patients (52%) were successfully treated by embolization and thus spared imminent surgery. Multiple variables were compared between those who were successfully treated by embolization and those considered failures. Time to angiography was considerably shorter (2.5 vs. 5.8 days, P<0. 017) and fewer total units of packed red blood cells were used (14.6 vs. 34, P<0.003) in those who were successfully treated. There was also a strong trend toward using fewer units of packed red blood cells for transfusion prior to angiography (11.2 vs. 17.1, P<0.08). No differences were found that could be attributed to gastric vs. duodenal sources, number of comorbid diseases, organ failure, APACHE score, age, or whether active bleeding was found at angiography. A total of 20 patients (40%) died including 9 of 17 patients operated on in an attempt to salvage angiographic failure. In summary, angiographic embolization should be performed early in the course of bleeding in otherwise critically ill patients.

APACHE↗