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Biomedical subjects

E M Miller

Publications and source records attributed to E M Miller.

16 recordsLinked to original sources
PubMed1992

Radiosensitization by fluorodeoxyuridine: effects of thymidylate synthase inhibition and cell synchronization.

The combination of fluoropyrimidines and radiation has resulted in increased control of colorectal cancer in the clinic, but the basic mechanism of the interaction is not understood clearly. Preliminary work in our laboratory showed that 2-h exposures of HT 29 human colon carcinoma cells to relatively low levels of 5-fluorodeoxyuridine resulted in extended thymidylate synthase inhibition after the drug was removed (up to 30 h after treatment with 0.5 microM 5-fluorodeoxyuridine). The low cytotoxicity associated with this treatment simplified efforts to test the effects of extended thymidylate synthase inhibition on radiosensitivity of HT 29 cells. Although thymidylate synthase was completely inhibited at the end of the 2-h exposure, an increase in the radiosensitivity of the cells was not evident until 16 h after the removal of drug. Flow cytometric analysis showed that cells accumulated in early S phase over time, and the increase in radiation sensitivity of the entire population followed the increase of the proportion of cells in early S, a relatively radiosensitive phase of the cell cycle. This treatment schedule was compared with 24-h continuous exposure, and we found that the same maximum increase in radiosensitivity was achieved by both treatment strategies. However, more cytotoxicity was associated with continuous exposure. This study provides evidence that radiosensitization by 5-fluorodeoxyuridine is in part due to alteration of cell kinetics and redistribution of cells throughout the cycle. This information may be useful in the design of less toxic combined chemo- and radiotherapy treatment strategies by limiting systemic exposure to fluoropyrimidines.

Cell Cycle↗
PubMed1992

On the correlation of myopia and intelligence.

A pleiotropic relationship between intelligence and myopia has been shown to exist. Large eyes (as measured by axial length) have been shown to lead to myopia, and large brains have been shown to be more intelligent. I hypothesized that the myopia/intelligence relationship could arise because a single genetically controlled mechanism affects both brain size and eye size. This hypothesis has testable implications.

Adolescent↗
PubMed1992

Low pH does not affect the dose response for 5'-amino-5'-deoxythymidine modulation of IdUrd DNA incorporation and radiosensitization in a human bladder cancer cell line.

We report that coincubation of 647V cells for one cell cycle with low concentrations (30 microM) of 5'-amino-5'-deoxythymidine increased IdUrd DNA incorporation and radiosensitivity at low extracellular pH (pHe 6.8) in a fashion similar to treatment at normal pHe. IdUrd DNA incorporation is inhibited by high (300 microM) 5'-AdThd concentrations at both normal and low pHe (7.4 and 6.8), resulting in no significant radiosensitization. These results at low pHe were not anticipated based on previously published studies of 5'-AdThd modulation of thymidine kinase (TK) activity and nucleoside cellular uptake. Our results suggest that regulation of intracellular pH (pHi) during the course of one cell cycle negates the 5'-AdThd dose-dependent modulation of TK activity demonstrated previously. Flow cytometric measurement of pHi in 647V cells showed that normal pHi (pH 7.4) was maintained in 647V cells over a 12- to 24-h exposure to low pHe (pH 6.8). Thus the concomitant use of IdUrd and high concentrations of 5'-AdThd (> 30 microM) is unlikely to result in selective in vivo radiosensitization of human tumors under conditions which are intermittently or chronically acidic. However, low concentrations of 5'-AdThd may prove to be an effective in vivo modulator of IdUrd radiosensitization of human tumors under both normal and acidic conditions.

Cell Cycle↗
PubMed1992

Linear-quadratic analysis of radiosensitization by halogenated pyrimidines. I. Radiosensitization of human colon cancer cells by iododeoxyuridine.

Radiosensitization by iododeoxyuridine (IdU) is a method of enhancing cell killing in the radiotherapy of human cancers, especially for tumors that proliferate faster than the surrounding normal tissues, such as might appear in brain or liver. We have investigated in vitro the relationship between the amount of thymidine replacement by IdU and the resulting radiosensitization in two human colon cancer cell lines, HCT 116 and HT 29, with differing inherent sensitivities to X rays. The results show that an increase in the initial slope of the cell survival curve was the predominant mode of radiosensitization. In this situation, the emphasis on changes in the initial slope suggest the use of a survival curve model that contains the initial slope as a defined variable, which the traditional single-hit, multitarget model does not. We present our analyses mainly in terms of alpha (initial slope) and changes in surviving fraction at 2 Gy and also as a modified form of sensitizer enhancement ratio that describes the dose-modifying factor of IdU at a single radiation dose of 2 Gy (SER 2 Gy). Iododeoxyuridine is an effective radiosensitizer in both cell lines, but IdU appears especially effective in increasing the initial slope of the more radioresistant line, the HT 29 cells.

Cell Survival↗
PubMed1992

Linear-quadratic analysis of radiosensitization by halogenated pyrimidines. II. Radiosensitization of human colon cancer cells by bromodeoxyuridine.

As a continuation of the studies in Part I (Miller, Fowler, and Kinsella, Radiat. Res. 131, 000-000, 1992), which examined the radiosensitizing effects of iododeoxyuridine (IdU), similar experiments with bromodeoxyuridine (BrdU) were conducted concurrently to characterize its effects on the shape of the radiation survival curves of cells of two human colon cancer cell lines, HT 29 and HCT 116. The efficiency of radiosensitization by BrdU, expressed as a function of percentage thymidine replacement, was lower when compared to IdU in both cell lines. However, the major radiosensitizing effect of BrdU was manifest as an increase in the initial slope (alpha), just as observed for IdU. However, with BrdU, in contrast to IdU, an increase in curvature (repairable damage) was also evident. Cells of the more radiosensitive line, HCT 116, showed less sensitization by either BrdU or IdU than cells of the more radioresistant line, HT 29. These results were consistent with the proposed mechanism of radiosensitization being an increase in the single-hit character of low-LET radiation. It follows that the radiosensitizing effects of both analogs were largest in the low-dose region of the survival curve.

Bromodeoxyuridine↗
PubMed1990

Modulation of IdUrd-DNA incorporation and radiosensitization in human bladder carcinoma cells.

5' Amino-5'-deoxythymidine (5'-AdThd) has been demonstrated previously to antagonize dTTP-mediated feedback inhibition of purified thymidine kinase from 647V, a human bladder cancer cell line. Low concentrations of 5'-AdThd (3-30 microM) have also been shown to stimulate cellular uptake of iododeoxyuridine (IdUrd) in 647V cells at clinically relevant IdUrd concentrations (2 microM). We report that the combination of 30 microM 5'-AdThd plus 2 microM IdUrd results in a significant increase of IdUrd replacement of thymidine (dThd) (18%) in the DNA of 647V cells over that obtained by exposure to 2 microM IdUrd alone (7.9%). However, increasing the 5'-AdThd concentration to 300 microM inhibited the incorporation of IdUrd into DNA (3%). IdUrd-induced radiosensitization of 647V cells, as measured by clonogenic survival, was enhanced by coincubation with 30 microM 5'-AdThd, while 300 microM 5'-AdThd reduced the IdUrd radiosensitization. Additionally, radiation-induced single strand break generation when IdUrd was incorporated into 647V DNA, as measured by rapid alkaline elution, was also enhanced by coincubation with 30 microM 5'-AdThd, while 300 microM 5'-AdThd resulted in a decrease in the number of single strand breaks produced. In T24, another bladder cancer cell line, and SV-HUC-TT1, a tumorigenic cell line derived from SV-HUC, 3-10 microM 5'-AdThd was also able to enhance IdUrd replacement of dThd in DNA. However, no stimulation of dThd replacement by 5'-AdThd occurred in SV-HUC, a prototypic "normal" bladder urothelial cell line. Since 5'-AdThd is not a substrate for mammalian thymidine kinase and has little or no cytotoxicity in vitro and in vivo, it may be a selective modulator of IdUrd radiosensitization of human bladder carcinoma and should be tested in vivo.

Carbon Radioisotopes↗
PubMed1990

The use of VP16 and cisplatin in the treatment of Merkel cell carcinoma.

A 70-year-old male with regionally recurrent Merkel cell cancer obtained a complete remission with three cycles of VP16 and cisplatin. His response was consolidated with local radiation therapy. Two additional patients have been reported to have responded to the same combination. Chemotherapy consisting of either cyclophosphamide, vincristine, and doxorubicin or VP16 and cisplatin should be considered in locally recurrent Merkel cell cancer.

Aged↗
PubMed1989

Interaction of deoxyuridine with fluorouracil and dipyridamole in a human colon cancer cell line.

We have reported previously that dipyridamole increases the toxicity of 5-fluorouracil and alters fluorouracil metabolism in HCT 116 cells, producing a selective increase in fluorodeoxyuridine monophosphate (FdUMP) levels by blocking the efflux of fluorodeoxyuridine. Dipyridamole also blocks deoxyuridine efflux and prolongs the intracellular half-life of deoxyuridine monophosphate (dUMP). The significance of the effect of dipyridamole on FdUMP and dUMP levels was explored further. In cell growth experiments, 1-50 microM deoxyuridine enhanced the cytotoxicity of 5 microM fluorouracil in a dose-dependent manner, and greater than or equal to 10 microM deoxyuridine increased the augmentation of fluorouracil toxicity produced by 0.5 microM dipyridamole. The effect of deoxyuridine on [6-3H]fluorouracil metabolism was studied. After 4 hr, 25 microM deoxyuridine increased the amount of [3H]FdUMP formed 2- to 4-fold relative to that of fluorouracil +/- dipyridamole alone. The mechanism by which deoxyuridine increased FdUMP was examined by measuring the distribution of [2'-3H]deoxyuridine metabolites following exposure of 25 microM deoxyuridine +/- 5 microM fluorouracil. Tritium appeared in the FdUMP peak at 4 and 24 hr in cells exposed to fluorouracil and deoxyuridine, indicating that [3H]deoxyribose was transferred to fluorouracil. A large buildup of [3H]dUMP was seen in cells exposed to fluorouracil plus deoxyuridine for 4 and 24 hr compared to exposure to [3H]deoxyuridine alone, suggesting that dUMP may also inhibit catabolism of FdUMP. Since the increased FdUMP levels produced by dipyridamole did not appear to correlate with further depletion of thymidine triphosphate pools, the incorporation of [3H]fluorouracil metabolites into nucleic acids was monitored by cesium sulfate density centrifugation. Fluorouracil-RNA increased as a function of time (1, 2 and 13 pmol/10(6) cells after 4, 8 and 24 hr), but fluorouracil-DNA was detected only after 24 hr (0.5 pmol/10(6) cells). Dipyridamole however, did not appear to alter the pattern of incorporation of fluorouracil into either RNA or DNA. Perturbations of endogenous dUMP levels by fluorouracil and dipyridamole were then studied. In cells exposed to fluorouracil alone, dUMP pools were unchanged from control at 2 hr, but they had increased 9-fold by 4 hr (3362 pmol/10(6) cells). Simultaneous exposure to fluorouracil and dipyridamole resulted in a 1.5-fold (566 pmol/10(6) cells) and 13.6-fold (5049 pmol/10(6) cells) increase over control dUMP levels after 2 and 4 hr respectively. The dUMP pools continued to enlarge through 24 hr. The effect of fluorouracil on DNA fragility was examined.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Survival↗
PubMed1979

The angiographic features of extraabdominal desmoid tumors.

Extraabdominal desmoid tumors are nonencapsulated locally invasive neoplasms of fibrous tissue. The angiographic features include arterial stretching, neovascularity, and tumor staining (4 of 6 cases in this series). Although benign, these tumors are difficult to cure because they tend to recur locally.

Adolescent↗
PubMed1979

The role of computed tomography in the evaluation of neck masses.

Application of computed tomography (CT) to neck masses has received little attention. The authors reviewed 10 cervical masses studied with CT as well as conventional imaging modalities. CT was extremely useful in defining both the osseous and soft-tissue extent of the lesion. In several instances, CT was able to show the relationship of the tumor to the spinal canal. When combined with angiography, CT demonstrated the relationship of the major cervical vascular channels to the lesion. Pathological conditions included neurofibroma, chordoma, branchial cleft cyst, neuroblastoma, lymphoma, neurilemmoma, and metastatic carcinoma.

Adult↗
PubMed1979

Duodenal involvement with Crohn's disease: a spectrum of radiographic abnormality.

The clinical and radiographic features of 22 cases of duodenal Crohn's disease were analyzed. The presenting clinical findings in the majority suggested peptic disease rather than regional enteritis. There was no cases of isolated duodenal Crohn's disease but a spectrum of radiographic abnormalities was produced by duodenal involvement with Crohn's disease which simulated a variety of clinical entities. A radiographic examination of the small bowel or colon was useful to confirm a diagnosis of Crohn's disease when duodenal abnormalities were suggestive.

Adolescent↗
PubMed1978

Extra-axial posterior fossa lesions simulating intra-axial lesions on computed tomography.

Differentiation of extra- from intra-axial posterior fossa lesions is sometimes not possible on computed tomography. Six cases are presented wherein the lesion appeared to be intra-axial on computed tomograms yet angiographically and surgically proved to be extra-axial. False localization on computed tomography occurs with slowly growing masses which burrow into brain parenchyma.

Adult↗
PubMed1977

Dissociation of prelycopersene pyrophosphate synthetase from phytoene synthetase complex of tomato fruit plastids.

The partially purified phytoene synthetase enzyme complex obtained from tomato fruit plastids dissociates into two or more subunit species on chromatography in low ionic strength buffer on DEAE-cellulose. One of these subunits prelycopersene pyrophosphate synthetase, has a molecular weight of approximately 40,000, whereas the phytoene synthetase complex has a molecular weight of 200,000. The prelycopersene pyrophosphate synthetase catalyzes the conversion of isopentenyl pyrophosphate to geranylgeranyl and prelycopersene pyrophosphates. The identities of these substances were established by thin layer chromatography in several solvent systems. The formation of both geranylgeranyl and prelycopersene pyrophosphates by this enzyme supports earlier results with cruder enzyme systems which suggested that these compounds are intermediates in the synthesis of phytoene.

Carotenoids↗
PubMed1976

Cerebellar glioblastoma multiforme in an adult.

One of the few well documented cases of cerebellar glioblastoma multiforme in an adult is reported. In addition, to our knowledge, it is the first reported case in which the angiographic, pneumoencephalographic, nuclear scan and CAT data have been correlated. In this case the CAT scan proved the most sensitive in the demonstration of tumor.

Age Factors↗