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Biomedical subjects

D Murray

Publications and source records attributed to D Murray.

At least 289 records · Page 16Linked to original sources
PubMed1985

Kinetics of DNA cross-linking in normal and neoplastic mouse tissues following treatment with cis-diamminedichloroplatinum(II) in vivo.

The formation and repair of cis-diamminedichloroplatinum(II) (cis-DDP)-induced DNA cross-links in cells from a number of different mouse tissues, both normal and neoplastic, were compared in three different populations of animals, tumor-free mice and mice bearing a transplanted fibrosarcoma (either FSa or NFSa) in their thighs. Groups of mice were given i.v. injections of 4-12-mg/kg doses of cis-DDP, and the amount of cis-DDP-induced DNA cross-linking was determined at different times after injection using an adaptation of the alkaline elution technique. The degree of cross-linking in each tissue was linearly related to the dose of cis-DDP at either 6 or 24 h after injection and varied significantly among the different tissues, with FSa, NFSa, kidney, and liver showing the highest level of cross-linking of the tissues studied. The relative contributions of DNA-interstrand and DNA-protein cross-links to the elution profiles were estimated by proteinase K (PK) digestion. At either 6 or 24 h after injection with cis-DDP, the rate of elution of the DNA was substantially increased by PK, indicating a large contribution of DNA-protein cross-links. This effect was observed in all tissues studied, although the proportion of PK-resistant lesions appeared to vary from tissue to tissue, liver and spleen showing a significantly lower proportion of DNA-interstrand to total cross-links than either of the tumors. For liver, virtually no interstrand cross-links could be detected after PK treatment. The kinetics of the repair of cis-DDP-induced DNA cross-linking in these tissues were also compared. In cells from tumor-free animals, the amount of total (DNA-interstrand plus DNA-protein) cross-linking increased gradually, reaching a maximum after about 6 h; however, little evidence of repair of these lesions was observed in any of these normal tissues. In fact, the degree of cross-linking tended to increase somewhat between 6 and 24 h after injection. The kinetics of cross-linking in cells isolated from the FSa tumor were very different; while there was an initial increase in cross-linking up to 6 h, these lesions were subsequently repaired, although at a somewhat slower rate than has been reported for cultured mammalian cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Colonic carcinoma associated with an abnormal collagen table. Collagenous colitis.

A case of cecal adenocarcinoma with the typical histopathologic features of collagenous colitis throughout the resected colon is described in a 67-year-old woman. Collagenous colitis has not previously been reported in association with adenocarcinoma of the colon and the relationship of these findings appears to be unprecedented. A review of 100 randomly selected Duke's B adenocarcinomas of the colon revealed no similar case.

Adenocarcinoma↗
PubMed1984

DNA damage produced by combined hyperglycemia and hyperthermia in two mouse fibrosarcoma tumors in vivo.

In this study we used alkaline elution to examine DNA damage produced in two murine fibrosarcomas after hyperthermia (42 degrees C), with or without preinduced hyperglycemia. The work was stimulated by a recent report that pretreatment of mice with glucose prior to hyperthermia decreased the growth rate in a similar fibrosarcoma tumor. The intercellular tumor pH dropped from its resting value of 7.1 to a value of 6.6 at 1.5 hr after a single injection of glucose. While treatment with either glucose alone or heat alone produced very little detectable damage, the combination of these two agents resulted in marked degradation of tumor DNA isolated immediately after treatment. DNA degradation was accompanied by a simultaneous decrease in cell viability; thus, direct cell killing and subsequent nuclease or lysosomal enzyme activity are probably involved. We also tested whether hyperglycemia combined with hyperthermia influenced the DNA-DNA crosslinking induced by subsequent cyclophosphamide (Cy) treatment. Because of the extensive degradation caused by the pretreatment alone under the conditions used in these initial experiments, we were not able to quantitate with validity the amount of Cy-induced crosslinking. However, damage in viable cells may presumably interact with the subsequent Cy treatment to produce further selective cell killing in the tumor.

Animals↗
PubMed1984

Colitis cystica profunda occurring in a radiation-induced colonic stricture.

Localized colitis cystica profunda developed in a fibrotic radiation-induced colonic stricture 17 years after pelvic radiation for squamous carcinoma of cervix. This uncommon pathologic entity must be distinguished from invasive adenocarcinoma of colon, and colonic radiation injury should be included with other conditions associated with colitis cystica profunda.

Colitis↗
PubMed1984

Effect of misonidazole pretreatment on nitrogen mustard-induced DNA cross-linking in mouse tissues in vivo.

In the present study we have used the alkaline elution technique to study the effect of misonidazole (MISO) on the initial amount of DNA cross-linking in various normal and neoplastic tissues of C3H mice treated with nitrogen mustard (HN2) in vivo. Tissue samples for analysis of the cross-links were prepared 1 h after injection with HN2 to minimize the effect of subsequent repair processes on the yield of lesions. For mice receiving HN2 alone, the greatest level of cross-linking was found in spleen and jejunum, with the liver showing the lowest level. In animals that had been pretreated with MISO (1 mg g-1, i.p.) for 0.5 h prior to injection with HN2, the amount of cross-linking in the spleen and jejunum was not affected by MISO; however, in all other tissues that were examined, cross-linking was enhanced by MISO to a varying extent depending on the specific tissue. The greatest enhancement was observed in the liver (X 6) and kidney (X 3.1), both of these tissues showing a greater enhancement than either of the two fibrosarcomas. The potentiation of HN2 cross-linking in a particular tissue correlated well with two cellular processes that are known to be nitroreduction-dependent in vitro, namely, the degree of MISO-induced GSH depletion and the binding of MISO to cellular macromolecules. Thus, the potentiation of cross-linking in normal tissues such as liver and kidney, and by inference in tumours, may be intimately related to the generation and/or accumulation of nitro-reduced MISO metabolites in those tissues.

Animals↗
PubMed1984

Ineffectiveness of adjuvant chemotherapy using DTIC and cyclophosphamide in patients with resectable metastatic melanoma.

A randomized, prospective trial of adjuvant chemoimmunotherapy was compared in a group of 136 patients with melanoma after complete surgical resection of advanced regional metastasis (stage III) or isolated distant metastasis (stage IV). All patients received a 2-year course of nonspecific adjuvant immunotherapy of subcutaneous injections of Corynebacterium parvum (4 mg/m2 divided among the four extremities in 1- to 2-week cycles). Half of the patients also received a 6-month course of dimethyl triazeno imidazole carboxamide (DTIC) plus cyclophosphamide chemotherapy (each at 600 mg/m2 administered intravenously every 3 weeks for nine cycles) while the other half received no chemotherapy. Analysis of the data showed that adjuvant chemotherapy did not provide any demonstrable therapeutic effect, either in terms of disease-free survival or overall survival. No benefit was observed in subgroups of patients categorized by disease stage, site of metastasis, or sex. The drugs did cause a substantial rate of morbidity, however, since 42% of the patients had severe nausea and vomiting, while 13% had hair loss. The C. parvum was well tolerated in almost all patients. This is a particularly high-risk group for subsequent metastases since only 24% of the patients were free of disease for 1 year and 12% after 2 years. Adjuvant DTIC and cyclophosphamide had no observable therapeutic effect on this population of high-risk patients with melanoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

The efficiency of DNA strand-break repair in two fibrosarcoma tumors and in normal tissues of mice irradiated in vivo with X rays.

We have used alkaline elution to study the repair of X-ray-induced DNA strand breaks in vivo in two fibrosarcoma tumors and in several normal mouse tissues after whole-body irradiation of mice with 10-12.5 Gy of X rays. Both tumors were found to repair damage significantly faster and to a greater extent than any of the normal tissues, so that by 2 hr after irradiation the level of damage in both tumors was indistinguishable from unirradiated control values. Of the normal tissues studied, liver repaired the fastest. The kinetics for the other normal tissues were essentially the same, showing an appreciable level (7-16%) of unrepaired lesions still evident after 2 hr. Even as late as 12 hr there was a significant amount of residual damage in some tissues, with testes and spleen showing the greatest level (ca. 15%). The repair kinetics for each tissue were not appropriately described by a sum of two exponentials. In contrast, previously reported data for many homogeneous mammalian cell systems in vitro and for some tissues in vivo have shown biphasic repair kinetics. This difference may be related to heterogeneity of both cell type and environment within the tissue populations used in the investigation. The faster repair of DNA strand breaks by tumor cells relative to cells from normal tissues was not readily explainable in terms of such radiobiological parameters as overall tissue oxygenation or sulfhydryl content. Rather, it appears that the degree of differentiation of the cells within the tissue population may be a major determinant of repair proficiency. Based on a model incorporating a competition between repair and fixation of sublethal lesions, these data are consistent with the idea that tumor cells may have a repair, and hence survival, advantage over normal cells in response to ionizing radiation.

Animals↗
PubMed1984

Enhancement of the DNA cross-linking activity of nitrogen mustard by misonidazole and diethyl maleate in a mouse fibrosarcoma tumor in vivo.

We have used the technique of alkaline elution to determine the amount of nitrogen mustard (HN2)-induced DNA cross-linking in a murine fibrosarcoma tumor in vivo. Mice were either treated with HN2 directly or were pretreated with misonidazole (MISO) or diethyl maleate prior to injection with HN2. Two types of HN2-induced DNA lesions were detected, namely, proteinase K-sensitive and -resistant cross-links. Pretreatment with MISO did not appear to affect the ratio of the two types of lesion. In mice treated with HN2 alone, the amount of cross-linking reached a high level by 0.5 hr postinjection, after which these lesions were repaired, 62% of cross-links being removed between 0.5 hr and 6 hr postinjection. Pretreatment of mice with MISO resulted in substantial alterations in both the magnitude and time course of cross-linking during the first few hr after injection of HN2. Both MISO and diethyl maleate enhanced the number of cross-links formed at 0.5 hr postinjection. Furthermore, in MISO-pretreated mice, only 18% of the cross-links present at 0.5 hr had been removed by 6 hr postinjection. This early enhancement is possibly related to glutathione depletion resulting in reduced intracellular inactivation of HN2. Since repair processes were determined not to be saturated at the level of lesions under study, these data suggest that, in addition to the initial glutathione depletion resulting in an increased burden of damage, MISO may also inhibit DNA repair processes, possibly via a hypoxia-dependent interaction between MISO reduction products and DNA or repair enzymes. Assuming that DNA cross-linking is related to the cytotoxicity of HN2, these effects may account for the MISO enhancement of HN2 toxicity toward various biological systems which have been reported previously. It appears that chemosensitization may result from a variety of factors, with the relative importance of each factor depending on the particular drug being used.

Animals↗
PubMed1983

An unusual autoimmune hemolytic anemia in a patient with immunoblastic sarcoma.

This report describes a patient with immunoblastic sarcoma and autoimmune hemolytic anemia with reticulocytopenia and red cell hypoplasia. Both IgG and IgM red cell autoantibodies were present in the patient's serum, and both antibodies had the uncommon specificity of anti-IT. This report appears to be the first to describe IgG auto anti-IT and autoimmune hemolytic anemia in a patient who did not have Hodgkin's disease; the laboratory findings and clinical course are described. The reticulocytopenia and red cell hypoplasia may have been immunologically mediated. The patient responded to plasma exchange, corticosteroids, and chemotherapy.

Anemia, Hemolytic, Autoimmune↗
PubMed1983

Metastatic malignant melanoma of unknown primary origin: a study of 30 cases.

Thirty patients with metastatic malignant melanoma of unknown primary origin treated at Emory University Clinic between 1940 and 1975 are presented. This group represents the 4.4% of all melanomas treated during the same period of time at Emory. Nineteen (63.3%) patients had nodal metastases only, and they were handled by radical lymphadenectomy of the involved area. The remaining 11 patients presented with lung or widespread subcutaneous metastatic disease and treated with biopsy and radiotherapy or chemotherapy. The former group experienced 28.6% five- and ten-year actuarial survival while patients with lung metastases succumbed within four months after diagnosis. Spontaneous regression of a typical melanoma skin lesion has been reported in three patients prior to development of metastatic disease.

Adult↗
PubMed1983

Increased incidence of experimental colon cancer associated with long-term metronidazole therapy.

Using the well-established DMH model for colon neoplasia, we demonstrated that a high-fiber diet pair-fed to animals was associated both with certain changes in bacterial profile and with protection against experimental colon neoplasia. The addition of metronidazole on a long-term basis to both high- and low-fiber diets did not alter stool bacteroides counts as expected and was associated with an apparent cocarcinogenic effect. Concern exists among surgeons and gastroenterologists as to whether metronidazole places their patients at risk. The status of long-term metronidazole therapy for patients with Crohn's disease is a pertinent example. In view of our findings, it is important to further elucidate the metabolism of metronidazole in both the rat and human gut.

1,2-Dimethylhydrazine↗
PubMed1983

Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo.

The technique of alkaline elution has been adapted for the study of drug-induced DNA cross-link formation in vivo. Pretreatment with misonidazole (MISO) enhances the number of cross-links formed in a fibrosarcoma and in the spleen and gut of mice for periods up to 48 h following a single injection of melphalan (MEL). The tumour was sensitized by a greater factor (2.05) than either of the normal tissues (enhancement factor 1.4-1.5). This enhancement did not appear to be related to inhibition of the repair of actual cross-links. Rather, the effect was explicable in terms of one of two alternative models. Firstly, MISO pretreatment could result in a greater amount of binding of MEL to DNA at early times after injection. This may be the result of altered pharmacokinetics of MEL, or of enhanced intracellular uptake of MEL due to MISO pretreatment. Secondly, MISO may exert its affect by inhibition of the repair of cross-links or monoadducts at early times post-injection, which would not be observed in this study. The possible involvement of glutathione depletion in chemosensitization by MISO was investigated by comparison with the effect of diethyl maleate (DEM), a known thiol-depleting reagent. Glutathione depletion, while perhaps being important, could not account for all of the effects observed.

Animals↗
PubMed1982

Subchronic toxicity of chlorine dioxide and related compounds in drinking water in the nonhuman primate.

Subchronic toxicities of ClO2, NaClO2, NaClO3 and NH2Cl were studied in the African Green monkeys (Cercopithecus aethiops). The chemicals were administered in drinking water during 30-60 days subchronic rising dose protocols. The only unexpected and significant toxic effect was elicited by ClO2; this chemical inhibited thyroid metabolism in the animals at a dose of ca. 9.0 mg/kg/day. A statistically significant decrease of serum thyroxine occurred after the fourth week of exposure to 100 mg/l.concentration. The extent of thyroid suppression was dose dependent in each individual monkey, and was reversible after cessation of exposure. NaClO2 and NaClO3 failed to elicit similar effects in doses up to ca. 60 mg/kg/day. Also, NaClO4 or NH2Cl did not cause T-4 suppression in doses of 10 mg/kg/day. The selective thyroid effect of ClO2 was unexplained and it appeared to be paradoxical since ClO2 was rapidly reduced by the oral and gastric secretions to nonoxidizing species (presumably Cl-). No evidence of thyroid effects were detected in the serum of human volunteers who ingested approximately 1 mg/l. of ClO2 in drinking water as a result of routine use in the community water treatment process. Sodium chlorite induced dose-dependent oxidative stress on hematopoesis, causing decreased hemoglobin and red cell count and increased methemoglobin content. At the same time, serum transaminase (SGPT) levels showed significant subclinical elevation. The hematologic effects of NaClO2 rebounded during exposure indicating compensatory hemopoietic activity taking effect during oxidative stress. Sodium chlorate and chloramine did not induce detectable hematologic changes in the animals.

Animals↗