Search PubMed⌕ Search

Biomedical subjects

C N Coleman

Publications and source records attributed to C N Coleman.

At least 55 records · Page 3Linked to original sources
PubMed1996

Role of interstitial radiotherapy in the management of clinically organ-confined prostate cancer: the jury is still out.

PURPOSE AND DESIGN: To discuss the evolution of the use of brachytherapy in the treatment of clinically organ-confined prostate cancer and to review modern techniques, results of therapy, and optimal patient selection criteria. RESULTS: Using modern localization and immobilization techniques, interstitial prostate radiotherapy for patients with a prostate-specific antigen (PSA) level less than 10 ng/mL yields an at least 87% rate of freedom from biochemical relapse at 3 years, which is numerically equivalent to results achieved with external-beam radiotherapy or radical prostatectomy. With a minimum median follow-up time of 24 months, 81% to 85% (2-year actuarial and 3-year crude) potency rates have been reported concomitant with 2-year actuarial rates of 12% for grade > or = 2 rectal complications and 10% for grade > or = 3 urethral complications. CONCLUSION: The combination of clinical stage, PSA level, and biopsy Gleason sum allows for selection of patients with the highest probability of having all of the prostate cancer encompassed by the high-dose implant volume, while simultaneously respecting the normal-tissue tolerance doses of the juxtaposed normal tissues (rectum and bladder). In particular, patients with nonpalpable (T1c) lesions, a biopsy Gleason sum < or = 6 (ideally < or = 4), and a PSA level less than 10 ng/mL represent the optimal implant candidates. Differential loading of the implant away from the geometric center and not accepting patients with large prostate glands (> or = 60 cm3) or history of a transurethral resection of the prostate (TURP) as implant candidates, may reduce urethral toxicity. Further follow-up evaluation of prostate cancer patients treated with interstitial radiotherapy will verify if favorable potency preservation rates and rates of freedom from biochemical failure equivalent to those achieved with radical prostatectomy or external-beam radiation therapy are maintained.

Actuarial Analysis↗
PubMed1996

Effect of BSO and etanidazole on neurofilament degradation in neonatal rat spinal cord cultures.

Peripheral neuropathy is the major dose-limiting toxicity of the hypoxic cell sensitiser, etanidazole. Previous work from this laboratory using culture neuronal cell lines suggested that nitroimidazole-induced degradation of neurofilament proteins might be the critical biological event mediating this neurotoxicity. The purpose of the present study was to develop the neurofilament degradation assay in an organotypic spinal cord culture system with the goal of developing strategies for optimising sensitiser efficacy as well as ameliorating nitroimidazole-induced neurotoxicity. Spinal cord cultures were treated with etanidazole and neurofilament protein degradation was analysed by immunoblot analysis. Spinal cord cultures exposed to etanidazole exhibited a dose-dependent loss of parent neurofilament proteins, with concomitant appearance of low molecular weight degradation products. The potential neurotoxic effect of L, S-buthionine sulphoximine (BSO), a compound that enhances the radiosensitising effectiveness of 2-nitroimidazoles, was also screened in this assay system. BSO alone, at concentrations up to 100 microM, did not promote neurofilament degradation. BSO (20 microM) enhanced the effect of etanidazole on neurofilament degradation by a dose-modifying factor of 1.6 +/- 0.5. Since 20 microM BSO is expected to enhance etanidazole radiosensitisation of hypoxic cells by a larger factor, this suggests that a therapeutic gain could be achieved using BSO in combination with etanidazole in radiation therapy.

Animals↗
PubMed1996

Biologic basis for radiation oncology.

Improved understanding of the underlying biologic mechanisms that pertain to radiation oncology is providing an explanation for the cellular and tissue responses to ionizing radiation and is leading to the potential for novel therapeutic strategies. Among the areas of intensive investigation are: DNA recombination and repair, signal transduction, gene regulation, apoptosis, the cellular stress response, and the effect of the tumor microenvironment. These new biologic concepts, coupled with the superior technical capabilities now available for treatment delivery, are paving the way for new clinical approaches to improving both the quality and quantity of life for the cancer patient.

Apoptosis↗
PubMed1996

Lisofylline as a modifier of radiation therapy.

Lisofylline is a new methylxanthine. The potential of lisofylline to enhance the response to ionizing radiation of the EMT-6 murine mammary carcinoma in vitro and in vivo was assessed and compared with pentoxifylline. Addition of lisofylline (100 microM) or pentoxifylline (100 microM) from the time of radiation exposure and throughout the time of colony formation did not alter the response of normally oxygenated EMT-6 cells to gamma-radiation delivered at 0.76 Gy/min or 12.3 Gy/min. The dose modifying factor for hypoxic EMT-6 cells by lisofylline or pentoxifylline and radiation delivered at 0.76 Gy/min was 2.3. Higher dose rate radiation (12.3 Gy/min) was more cytotoxic toward hypoxic EMT-6 cells than lower dose rate radiation. The dose modifying factor produced by lisofylline in the high dose rate radiation setting was 1.2. In vivo, using the tumor cell survival assay, lisofylline decreased the shoulder of the radiation survival curve (0.76 Gy/min) by a factor of 1.7 +/- 0.2 while pentoxifylline did not. In the tumor growth delay assay, administration of multiple doses of lisofylline or pentoxifylline along with single dose radiation (0.76 Gy/min) was 1.3, while the radiation dose modifying factor for lisofylline or pentoxifylline administered by continuous infusion was 1.5. Overall, lisofylline was a more effective modifier of gamma-radiation therapy than pentoxifylline, and further investigation of lisofylline in this setting is warranted.

Animals↗
PubMed1996

Suramin increases p53 protein levels but does not activate the p53-dependent G1 checkpoint.

Suramin is an antineoplastic agent which has a cytostatic effect on both normal and tumor-derived cells. We have investigated whether the induction of growth arrest by suramin requires the p53 protein, a tumor suppressor gene product involved in the initiation of growth arrest following DNA damage. Activation of the p53 protein by genotoxic agents causes increased p53 protein levels and p53-dependent transcription of the p21 gene. The p21 protein then inhibits cyclin-dependent kinases, initiating G1 arrest. Exposure of NIH-3T3 cells to suramin caused a rapid (1-2 h) increase in the level of p53-DNA-binding activity. Flow cytometric analysis indicated that suramin arrested NIH-3T3 cells in G0-G1. However, suramin did not increase the p53-dependent transcription of the p21 gene or inhibit cyclin-dependent kinase 2 kinase activity. If NIH-3T3 cells were exposed to radiation or suramin plus radiation, p21 mRNA levels were increased and cyclin-dependent kinase 2 kinase activity was inhibited, indicating that suramin does not block the cells' ability to increase p21 levels. To determine whether the G0-G1 arrest induced by suramin required p53, NIH-3T3 cells transfected with a dominant negative mutant p53 gene to eliminate wild-type p53 function (NMP cells) were exposed to suramin. NMP cells still exhibited G0-G1 arrest after suramin treatment. Suramin increases p53 protein levels, but fails to increase p21 mRNA levels or to activate the G1 checkpoint. These data suggest that suramin induces growth arrest in NIH-3T3 cells by a mechanism that is independent of cellular p53 status.

3T3 Cells↗
PubMed1995

Mantle irradiation alone for selected patients with laparotomy-staged IA to IIA Hodgkin's disease: preliminary results of a prospective trial.

PURPOSE: To determine the feasibility of omitting prophylactic paraaortic irradiation in selected patients with laparotomy-staged (pathologically staged [PS]) IA to IIA Hodgkin's disease. PATIENTS AND METHODS: We initiated a prospective single-arm trial in October 1988 to study the role of mantle irradiation alone in selected PS IA to IIA patients with Hodgkin's disease. A total of 37 patients have been entered onto this trial. Entrance criteria included nodular sclerosis (NS) or lymphocyte predominance (LP) histology, absence of B symptoms, disease limited above the carina, and a negative laparotomy. Results of treatment of 23 patients in the prospective trial, monitored off treatment for > or = 1 year, are presented. Twenty-three additional PS IA to IIA patients, treated with mantle irradiation alone from 1970 to 1987, were analyzed as a comparison group. The median follow-up durations were 32 and 113 months, respectively, for the two groups. RESULTS: The 4-year actuarial rates of freedom from relapse and overall survival are 83% and 100%, respectively, for the prospective trial. The 10-year actuarial rates of freedom from relapse and overall survival are 83% and 89%, respectively, for retrospectively studied patients. There have been five recurrences among 46 patients who received mantle irradiation alone, all with a component of relapse below the diaphragm. CONCLUSION: These early results support the use of mantle irradiation alone in selected PS IA to IIA patients with NS or LP histology. Relapses, although rare, have occurred predominantly below the diaphragm. This suggests the need for continued long-term surveillance of abdominal and pelvic nodes in this group of treated patients.

Actuarial Analysis↗
PubMed1995

Effect of cell cycle stage, dose rate and repair of sublethal damage on radiation-induced apoptosis in F9 teratocarcinoma cells.

There are at least two different modes of cell death after treatment with ionizing radiation. The first is a failure to undergo sustained cell division despite metabolic survival, and we refer to this end point as "classical reproductive cell death." The second is a process that results in loss of cell integrity. This second category includes cellular necrosis as well as apoptosis. Earlier studies in our laboratory showed that the predominant mechanism of cell death for irradiated F9 cells is apoptosis, and there is no indication that these cells die by necrosis. We have therefore used cells of this cell line to reassess basic radiobiological principles with respect to apoptosis. Classical reproductive cell death was determined by staining colonies derived from irradiated cells and scoring colonies of less than 50 cells as reproductively dead and colonies of more than 50 cells as survivors. Cells that failed to produce either type of colony (detached from the plate or disintegrated) were scored as having undergone apoptosis. Using these criteria we found that the fraction of the radiation-killed F9 cells that died by apoptosis did not vary when cells were irradiated at different stages of the cell cycle despite large variations in overall survival. This suggests that the factors that influence radiation sensitivity throughout the cell cycle have an equal impact on apoptosis and classical reproductive cell death. There was no difference in cell survival between split doses and single doses of X rays, suggesting that sublethal damage repair is not a factor in radiation-induced apoptosis of F9 cells. Apoptosis was not affected by changes in dose rate in the range of 0.038-4.96 Gy/min.

Apoptosis↗
PubMed1995

Modulation of radiation-induced apoptosis and G2/M block in murine T-lymphoma cells.

Radiation-induced apoptosis in lymphocyte-derived cell lines is characterized by endonucleolytic cleavage of cellular DNA within hours after radiation exposure. We have studied this phenomenon qualitatively (DNA gel electrophoresis) and quantitatively (diphenylamine reagent assay) in murine EL4 T-lymphoma cells exposed to 137Cs gamma irradiation. Fragmentation was discernible within 18-24 h after exposure. It increased with time and dose and reached a plateau after 8 Gy of gamma radiation. We studied the effect of several pharmacological agents on the radiation-induced G2/M block and DNA fragmentation. The agents which reduced the radiation-induced G2/M-phase arrest (caffeine, theobromine, theophylline and 2-aminopurine) enhanced the degree of DNA fragmentation at 24 h. In contrast, the agents which sustained the radiation-induced G2/M-phase arrest (TPA, DBcAMP, IBMX and 3-aminobenzamide) inhibited the DNA fragmentation at 24 h. These studies on EL4 lymphoma cells are consistent with the hypothesis that cells with radiation-induced genetic damage are eliminated by apoptosis subsequent to a G2/M block. Furthermore, it may be possible to modulate the process of radiation-induced apoptosis in lymphoma cells with pharmacological agents that modify the radiation-induced G2/M block, and to use this effect in the treatment of patients with malignant disease.

2-Aminopurine↗
PubMed1994

Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression.

Recent studies demonstrate the relationship of microvessel density to malignant progression in breast cancer (N. Weidner, J. P. Semple, W. R. Welch, and J. Folkman, N. Engl. J. Med., 324: 1-8, 1991), underscoring the importance of angiogenesis in this tumor. Crucial in tumor angiogenesis are the paracrine actions of tumor-secreted factors (e.g., vascular endothelial growth factor), which have been thought to derive from the tumor epithelial cells themselves. We demonstrate that in response to hypoxic conditions, human mammary fibroblasts dramatically up-regulate vascular endothelial growth factor mRNA and increase vascular endothelial growth factor protein levels in accordance with the degree of oxygen deprivation. Thus, mammary stromal cells, only recently considered in the regulation of breast carcinomas, may play a hitherto unrealized role in breast cancer angiogenesis.

Breast↗
PubMed1994

Protection against SR 4233 (Tirapazamine) aerobic cytotoxicity by the metal chelators desferrioxamine and tiron.

PURPOSE: Metal chelating agents and antioxidants were evaluated as potential protectors against aerobic SR 4233 cytotoxicity in Chinese hamster V79 cells. The differential protection of aerobic and hypoxic cells by two metal chelators, desferrioxamine and Tiron, is discussed in the context of their potential use in the on-going clinical trials with SR 4233. METHODS AND MATERIALS: Cytotoxicity was evaluated using clonogenic assay. SR 4233 exposure was done in glass flasks as a function of time either alone or in the presence of the following agents: superoxide dismutase, catalase, 5,5-dimethyl-1-pyrroline, Trolox, ICRF-187, desferrioxamine, Tiron (1,2-dihydroxybenzene-3,5-disulfonate), and ascorbic acid. Experiments done under hypoxic conditions were carried out in specially designed glass flasks that were gassed with humidified nitrogen/carbon dioxide mixture and with a side-arm reservoir from which SR 4233 was added to cell media after hypoxia was obtained. Electron paramagnetic resonance studies were also performed. RESULTS: Electron paramagnetic resonance and spectrophotometry experiments suggest that under aerobic conditions SR 4233 undergoes futile redox cycling to produce superoxide. Treatment of cells during aerobic exposure to SR 4233 with the enzymes superoxide dismutase and catalase, the spin trapping agent DMPO, the water-soluble vitamin E analog Trolox, and the metal chelator ICRF-187 provided little or no protection against aerobic SR 4233 cytotoxicity. However, two other metal chelators, desferrioxamine and Tiron, afforded significant protection against aerobic SR 4233 cytotoxicity (protection factors at 50% survival were 3.8 and 3.1, respectively), while exhibiting minimal protection to hypoxic cells treated with SR 4233. CONCLUSIONS: One potential mechanism of aerobic cytotoxicity is redox cycling of SR 4233 with molecular oxygen resulting in several potentially toxic oxidative species that overburden the intrinsic intracellular detoxification systems such as superoxide dismutase, catalase, and glutathione peroxidase. This study identifies two metal chelating agents, desferrioxamine and Tiron, that were able to protect against aerobic but not hypoxic SR 4233 cytotoxicity.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1994

SR-4233 (Tirapazamine) acts as an uncoupler of oxidative phosphorylation in human MCF-7 breast carcinoma cells.

SR-4233 (Tirapazamine) is a hypoxic cell selective cytotoxic agent currently in Phase I clinical trial. Although SR-4233 is selectively cytotoxic toward hypoxic cells some cytotoxicity toward normally oxygenated cells also occurs. SR-4233 (500 microM, 1 h) killed about 70% of normally oxygenated and 99% of hypoxic human MCF-7 breast carcinoma cells. Using a polarographic chamber and a Clark O2 electrode the O2 consumption of MCF-7 cells was measured in the presence or absence of SR-4233 (500 microM) or other inhibitors or uncouplers of oxidative phosphorylation. MCF-7 cells exhibited increased O2 consumption in the presence of SR-4233 alone and after treatment with oligomycin but not after treatment with retenone. The pattern of O2 consumption observed after treatment with SR-4233 was very similar to that seen when the cells were treated with the classical uncoupler FCCP. After 1 h of exposure to SR-4233 (500 microM) the cells were not responsive to treatment with oligomycin or FCCP for at least 3 h, but by 24 h post exposure to SR-4233 the cells had regained responsiveness to both FCCP and oligomycin. These results indicate that in normally oxygenated cells SR-4233 acts as an uncoupler of oxidative phosphorylation so that the cells continue to consume O2 but no ATP is produced. This condition can lead to ATP depletion especially in respiration intensive tissues and may provide an explanation for the muscle cramping observed in some patients treated with SR-4233.

Adenocarcinoma↗
PubMed1994

Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas.

BACKGROUND: Despite optimal therapy with surgery and radiotherapy, the prognosis of patients with glioblastomas remains poor. Stereotactic brachytherapy involves the accurate placement of radioactive isotopes within brain tumors, significantly increasing the dose of radiation that can be delivered to the tumor bed without substantial risk to surrounding normal tissue, potentially improving local tumor control and patient survival. METHODS: Between February 1987 and July 1993, the authors treated 56 patients with glioblastomas with stereotactic brachytherapy as part of their initial therapy. Patients underwent surgery, limited field external beam radiotherapy, and brachytherapy with temporary high-activity iodine 125 sources, giving an additional 50 Gy to the tumor bed. RESULTS: Median survival for patients undergoing brachytherapy was 18 months compared with 11 months for a matched brachytherapy control group with similar clinical and radiologic features (P < 0.0007). Survival rates at 1, 2, and 3 years after diagnosis of 83%, 34%, and 27%, respectively, for patients receiving brachytherapy were significantly increased compared with survival rates of 40%, 12.5%, and 9%, respectively, for control subjects. Thirty-six patients (64%) underwent reoperation for symptomatic radiation necrosis from 3 to 42 months (median, 11 months) after brachytherapy. The median survival of patients undergoing reoperation was 22 months compared with 13 months for those who did not have further surgery (P < 0.02). Thirty-five percent of patients relapsed locally within the brachytherapy target volume, whereas 65% had marginal or distant relapses. CONCLUSIONS: Brachytherapy may improve local tumor control and prolong survival when used in the initial treatment of selected patients with glioblastomas.

Adolescent↗
PubMed1994

Combined-modality therapy of esophageal cancer with radiotherapy, etanidazole, and cisplatin-fluorouracil, with or without surgery: neurotoxicity, other toxicities and outcome.

PURPOSE: To investigate whether etanidazole and cisplatin can be given safely together and to evaluate the relationship between incidence of peripheral neuropathy and cumulative exposure to etanidazole and cisplatin, as well as other toxicities and treatment outcome. METHODS AND MATERIALS: Thirty-two previously untreated patients with locally advanced esophageal cancer were entered on a Phase I study of etanidazole combined with radiation therapy and chemotherapy. Cisplatin/5-FU (two cycles, weeks 1 and 4) and etanidazole (weeks 2, 3 and 5) were given concurrently with radiation therapy. Eligible patients then underwent surgical resection. All patients were scheduled to receive two additional cycles of cisplatin/5-FU chemotherapy after completion of radiation therapy (definitive arm) or surgery (preoperative arm). RESULTS: Of 19 fully evaluable patients, nine (47%) developed peripheral neuropathy. Six of six patients, 65 years or older, experienced peripheral neuropathy, compared with three of 13 patients less than 65 years old (p = .003). For patients younger than 65 years, two of the two patients with single dose area under the curve (AUC) > 4.0 mMhr experienced peripheral neuropathy, compared with one of 11 patients with single-dose AUC < 4.0 mMhr (p = .03). Grade 4 toxicity included neutropenia (23%) and thrombocytopenia (26%). No other Grade 4 toxicity was observed. The pathologic complete response rate in patients who underwent surgical resection was 29%. CONCLUSION: This regime of chemotherapy, radiotherapy, and etanidazole had acceptable toxicity. However, combining etanidazole and cisplatin appears to increase the risk of developing peripheral neuropathy for at least some categories of patients. Further studies of these interactions are needed.

Adenocarcinoma↗