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Biomedical subjects

W D Ensminger

Publications and source records attributed to W D Ensminger.

At least 55 records · Page 3Linked to original sources
PubMed1990

The effect of single versus double-strand substitution on halogenated pyrimidine-induced radiosensitization and DNA strand breakage in human tumor cells.

To better understand the mechanism underlying halogenated pyrimidine-mediated cytotoxicity and radiosensitization in human tumor cells, a study was undertaken to determine the influence of unifilar (one DNA strand) versus bifilar (both DNA strands) substitution of thymidine by the halogenated bases 5-iodo-2'-deoxyuridine (IdUrd) and 5-bromo-2'-deoxyuridine (BrdUrd) in HT29 human colon cancer cells. Unifilar labeling was obtained by incubating cells with IdUrd or BrdUrd for one doubling time. Cells were incubated for at least three doublings to approximate bifilar substitution. Only IdUrd caused significant cytotoxicity, which correlated with incorporation into DNA. Both BrdUrd and IdUrd were potent radiosensitizers. Radiosensitization was linearly correlated with incorporation of both bases regardless of the number of strands in which thymidine was substituted. In contrast, the relationship between radiosensitization and DNA double-strand breakage was critically dependent in the case of IdUrd, but not for BrdUrd, on whether substitution was unifilar or bifilar. These findings suggest that incorporation is the best predictor of radiation sensitivity, and that the induction of DNA double-strand breaks alone does not account for radiosensitization mediated by halogenated pyrimidines in these human tumor cells.

Bromodeoxyuridine↗
PubMed1989

Stability of trimetrexate, a new non-classical antifolate, in infusion solutions.

A prerequisite for the prolonged infusion of a drug via a totally implanted drug delivery system is that the drug solution must be sufficiently stable at physiological temperatures to endure the time intervals between drug replacement or pump refills. Consequently, the stability of the chemotherapeutic agents can influence the dosing accuracy and ultimately the achievement of the desired therapeutic goal. The chemical stability of the pharmaceutical preparation Trimetrexate (TMQ) glucuronate, a non-classical, lipophilic antifolate, has been characterized. Incubation of TMQ (prepared in sterile water to a concentration of 5.0 mg/ml) in sterile, amber glass vials at 37 degrees C for 56 days resulted in a degradation rate constant of 0.0134 +/- 0.002 day-1 and a half-life of 51.6 +/- 0.8 days. The major degradation product has been identified as (2,4-diamino-5-methyl-6-carboxaldehyde)quinazoline. Ten percent TMQ degradation would occur by 7.9 days of incubation under these conditions.

Chromatography, High Pressure Liquid↗
PubMed1989

Response of human HT-29 colorectal tumor cells to extended exposure to bromodeoxyuridine.

Effects of the extended exposure of a human colorectal tumor-cell line (HT-29) to bromodeoxyuridine (BrdUrd) were studied in anticipation of the clinical use of that agent to treat colorectal cancer, particularly as a regionally delivered radiosensitizer. We found that 72-h exposure to a concentration of BrdUrd that is estimated to be locally maintained in the liver (100 microM) was significantly cytotoxic with a 3-log reduction in survival. As measured by GC/MS-SIM method, incorporation of BrdUrd into DNA followed an unexpected time course in that continuous exposure to 10 microM BrdUrd resulted in maximal incorporation at 3 days, after which the extent of incorporated analog fell significantly (despite daily changes of the medium). This finding was apparently due to a greater rate of loss of BrdUrd from the medium at later time points. Flow cytometric analysis using an anti-BrdUrd antibody (IU-4) revealed that antibody binding also peaked and fell off with time. However, at exposure times of greater than 24 h, the timing and extent of this decline were significantly different than had been indicated by the GC/MS method. These results indicate that the quantitative relationship between antibody staining and BrdUrd incorporation changes as drug-exposure time increases and that quantitative studies of anti-BrdUrd antibody binding must be interpreted with caution, especially when extended drug-treatment protocols have been used.

Bromodeoxyuridine↗
PubMed1989

5-Bromo-2'-deoxyuridine incorporation into DNA in hepatic VX2 tumor-bearing rabbits.

The halogenated pyrimidine 5-bromo-2'-deoxyuridine (BrdUrd) possesses both radiosensitizing and antimetabolite effects through its incorporation as a thymidine analog in replicating DNA. To evaluate the regional advantage for treatment of hepatic malignancy by hepatic arterial infusion, BrdUrd was infused into either the hepatic artery (HA) or a central vein (iv) in 26 rabbits with intrahepatic VX2 tumor. After a 24-hr constant rate infusion of 10, 20, or 40 mg/kg/24 hr, the percentage BrdUrd incorporation into the DNA of bone marrow, duodenal mucosa, liver, and hepatic VX2 tumor was measured by gas chromatography/mass spectrometry methods. VX2 tumor BrdUrd incorporation was greater by HA than by iv routes (P less than 0.001). At doses of 10 and 20 mg/kg/day, HA to iv BrdUrd incorporation ratios for VX2 tumor significantly exceeded those for bone marrow and duodenum (P less than 0.05). At appropriate dose rates, hepatic arterial administration of BrdUrd provides a regional advantage for DNA BrdUrd incorporation in the rabbit intrahepatic VX2 tumor.

Animals↗
PubMed1989

Combination chemo-radiation therapy for jaundice due to focal malignant obstruction of the major bile ducts.

Twenty patients with focal malignant obstruction of the major bile ducts (6 cholangiocarcinoma, 8 colorectal, 3 hepatoma, 2 unknown primary, and 1 gastric cancer) were treated on a protocol examining the toxicity and efficacy in relieving jaundice of external beam radiation therapy (4500 cGy in 300 cGy fractions) combined with continuous hepatic arterial (15 patients) or peripheral venous (5 patients) fluorouracil infusion. Toxicity of this regimen consisted of anorexia with mild nausea and vomiting in 55% of patients and gastric ulceration (responsive to medical management) in 15% of patients. One patient exhibited transient grade 2 hepatic toxicity and one had asymptomatic grade 4 leukopenia. Of 14 patients treated without prior biliary drainage, 8 exhibited a decrease in bilirubin levels from a mean of 14.5 mg/dl to 1.5 mg/dl. Four of six patients with biliary drainage catheters at the start of treatment were able to have them removed without reobstruction. For the 8 responding patients among those who did not have cholangiocarcinomas, the median response duration was 5 months with a median survival from treatment of 6.5 months. For the 4 responding patients with cholangiocarcinoma, the median response duration was 16 months with a median survival from treatment of 20 months. All responders did not have a return of jaundice due to reobstruction of the major ducts (until death or to the present). All responders who have died did so due to tumor progression outside of the treated field except for one who died of unrelated causes. The mean number of proven or presumed episodes of cholangitis per patient was virtually identical in those without (1.8) and those with stents/tubes (1.4, p = 0.561). This regionally focused combined modality cytotoxic therapy was able to relieve obstruction in the majority of patients without excess morbidity (including a lack of any detectable increase in sepsis). Thus, it appears feasible to consider randomized studies of this cytotoxic approach versus standard mechanical drainage procedures to define the relative risks and benefits of each.

Adult↗
PubMed1989

Modulation of liver tumor blood flow with hepatic arterial epinephrine: a SPECT study.

Changes in the relative arterial flow to hepatic tumors and adjacent normal liver, in response to varied doses of hepatic arterial epinephrine, were studied with single photon emission computed tomography. In 18 patients with known hepatic tumors, hepatic artery perfusion scans were obtained with the concurrent infusion of technetium-99m-labeled macroaggregated albumin and escalating doses of epinephrine (0-10 micrograms/min). Regions of interest were drawn around tumor and adjacent normal liver in three planes, and the average tumor-to-liver ratio (T:L) was calculated. In all 18 patients, there was a measurable baseline T:L perfusion advantage (range, 1.7-18.7; mean, 4.8). In 12 of 18 patients, this ratio increased with epinephrine (range, 1.1-53.6 times the baseline value; mean, 7.1). In six patients, no improvement in T:L could be demonstrated. In 14 patients the lung shunt index, a measurement of arteriovenous shunting, increased with escalating doses of epinephrine. This pilot study suggests that the infusion of epinephrine may improve the therapeutic index of certain regional therapies such as bolus drug infusions, hepatic arterial embolization, and radioactive microsphere therapy.

Epinephrine↗
PubMed1989

Unsatisfactory hepatic perfusion after placement of an implanted pump and catheter system: angiographic correlation.

Thirty-five patients with scintigrams showing unsatisfactory hepatic artery perfusion after surgical placement of an implanted pump and catheter system were examined with selective angiography (33 cases) or digital subtraction angiography (DSA) during which the contrast material was injected through the side port of the pump (six cases). In 34 of 35 cases, the cause of the unsatisfactory (either extrahepatic or incomplete) hepatic perfusion was defined. DSA was definitive in only two cases, in which extrahepatic flow through collateral vessels was demonstrated. The cause of the perfusion defect was hepatic artery thrombosis in 14 cases, extrahepatic flow through collateral vessels in 14 cases, a misplaced catheter in four cases, and a short proper hepatic artery without adequate length for mixing in two cases. Although hepatic artery perfusion scintigraphy is the primary tool for evaluation of hepatic perfusion after catheter placement, angiography plays an important role in treating the subset of patients with unsatisfactory hepatic perfusion.

Antineoplastic Agents↗
PubMed1988

Intra-arterial 5-bromo-2-deoxyuridine (BUdR) radiosensitization with external beam radiation in rhesus monkeys: toxicity study.

A primate toxicity study was performed to test the hypothesis that BUdR does not increase the likelihood of unilateral or bilateral central nervous system damage secondary to radiation therapy. BUdR, a halogenated pyrimidine analog is incorporated into DNA of dividing cells and sensitizes them to radiation. It is best given unilaterally, intra-arterially by continuous infusion because of its regional advantage (Rd) estimated to be between 11 and 16. Six rhesus monkeys were implanted with a Model 400 Infusaid pump perfusing the right internal carotid artery. Three of the six monkeys received intra-arterial (IA) BUdR infusion plus whole brain external beam radiation (6,000 R over 6 weeks) and three received radiation alone. The two BUdR treated animals completing radiation developed symmetric bilateral high signal aberrations on MRI in the frontal, parietal, and occipital centrum semiovale and corona radiata at nine months. At autopsy, confluent microinfarcts were found to correspond topographically to the MRI abnormalities. In the radiation alone group, two animals had normal MRI and autopsy while the third animal had bilateral MRI high signal aberrations develop sequentially with corresponding microinfarcts at autopsy. These changes were greater in severity than those seen in the BUdR treated animals. We support previous evidence that there is differential intraspecies sensitivity to radiation. We find that BUdR produces no unilateral potentiation of radiation toxicity.

Animals↗
PubMed1988

Dynamics of bromodeoxyuridine incorporation into DNA of squamous carcinoma cells during mid and late logarithmic growth.

Head and neck squamous carcinoma cell lines, UM-SCC 1, 5, 9, 11B, and 14B, were exposed in vitro to bromodeoxyuridine (BUdR) during logarithmic growth to determine the effects of drug concentration (0.01 to 10 microM) and duration of exposure (3, 7, and 10 days) on cell growth and on incorporation of BUdR into DNA. Concentrations of less than 1.0 microM were not growth inhibitory except with UM-SCC-11B. After 10 days of exposure to 5 microM BUdR, survival fractions for all lines ranged from 2 to 65% of controls. Replacement of thymidine by BUdR in DNA was assessed by gas chromatography/mass spectroscopy. Percentage replacement (% R) was described by the equation % R = 100 (C/t)s/[(C/t)50s + (C/t)s], where C is the concentration of BUdR (microM), t is the time in days, s is a constant, and (C/t)50 is a constant corresponding to % R = 50%. BUdR incorporation reached a time- and concentration-dependent maximum that, after 3 to 7 days of culture in 10 microM BUdR, ranged from 30 to 60% R. Subsequently, % R declined with time even though the cells were fed daily with fresh BUdR-containing medium.

Bromodeoxyuridine↗
PubMed1988

A simple method for long-term biliary access in large animals.

A simple method to obtain long-term access to the biliary tree in dogs and pigs is presented. In ten dogs and four pigs, a cholecystectomy was performed, the cystic duct isolated, and a catheter inserted into the cut end of the cystic duct. The catheter was connected to a subcutaneous infusion port, producing a closed, internal system to allow long-term access. The catheter placement was successful in three of the pigs and all of the dogs. Thirty-five cholangiograms were obtained in the 13 subjects by accessing the port with a 20 gauge Huber needle and injecting small amounts (4-10 mL) of contrast under fluoroscopic control. Cholangiograms were obtained up to four months after catheter placement without evidence for catheter failure or surgically induced changes in the biliary tree. This model provides a simple, reliable means to obtain serial cholangiograms in a research setting.

Animals↗
PubMed1988

Distinction of hepatic cavernous hemangioma from hepatic metastases with MR imaging.

Twenty-four hepatic cavernous hemangiomas and 91 metastases from a variety of hypovascular and hypervascular primary neoplasms were prospectively studied with magnetic resonance (MR) imaging. In addition to qualitative analysis, quantitative analysis of signal intensity ratios of lesion to normal liver was performed with images obtained with 500/28-30 (repetition time msec/echo time msec) and 2,000/28-150 sequences. Quantitative data did not improve the ability to distinguish hemangiomas from metastases in our series compared with qualitative analysis. Hypovascular metastases, such as colon carcinoma, could be differentiated from hemangioma more frequently (97.5%) than hypervascular endocrine metastases, such as islet cell tumor, carcinoid, and pheochromocytoma (61%). These findings indicate that the utility of MR imaging in differentiating hemangiomas from metastases is dependent on the histologic type of the primary neoplasm.

Diagnosis, Differential↗
PubMed1988

Intra-arterial bromodeoxyuridine radiosensitization and radiation in treatment of malignant astrocytomas.

Bromodeoxyuridine (BUdR), a nonhypoxic radiosensitizing drug, is a halogenated pyrimidine analog that is incorporated into the deoxyribonucleic acid of dividing cells in a competitive process with thymidine; BUdR also sensitizes these cells to radiation therapy. Neurons and glial cells have a very low mitotic rate. They will not incorporate BUdR and will not be sensitized. Bromodeoxyuridine is best delivered intra-arterially because of its regional advantage, calculated to be between 6 and 16. An 8-week BUdR infusion is delivered before and during radiation therapy through a permanently implanted pump with a catheter placed retrograde into the external carotid artery. Eighteen patients with malignant glioma (15 grade IV, and three grade III) were entered into a Phase I dose-escalation protocol with BUdR dosages ranging from 400 to 600 mg/sq m/day. The maximum dose that can be tolerated appears to be 400 mg/sq m/day for 8 weeks. The 18 patients entered in this study have a median Kaplan-Meier estimated survival time (+/- standard error of the mean) of 22 +/- 5 months with 11 patients still alive. Three patients are alive at 30, 29, and 21 months after diagnosis with no evidence of tumor on computerized tomography. There have been no vascular complications. Side effects in all patients have included anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, iritis, and nail ridging. Myelosuppression requiring dose reduction occurred in one patient. One patient had a Stevens-Johnson syndrome requiring termination of BUdR. It is concluded that intra-arterial BUdR may improve survival times in patients with malignant gliomas.

Adult↗
PubMed1988

Experience with subcutaneous infusion ports in three hundred patients.

Subcutaneous infusion ports (SIP) were inserted for chronic venous access during 329 procedures in 300 patients over the past five years at the University of Michigan Medical Center, with a total follow-up experience of 318 patient years. Seventy-four per cent of the SIP were surgically implanted while patients were hospitalized. The SIP were used for chemotherapeutic agents (83.0 per cent), blood products (29.0 per cent) or hyperosmolar total parenteral nutrition (8.5 per cent) and accessed a median of three occasions. Eighty-four per cent were used in an outpatient setting at least part of the time. Thirty-nine per cent of SIP were associated with complications, including local infection or sepsis (16.4 per cent), thrombosis of the catheter or central vein (9.7 per cent) and extravasation from the port secondary to needle dislodgement (6.4 per cent). The risk of complication was slightly higher in those SIP first used ten to 14 days after placement as compared with those used earlier or later (p less than 0.05). In 23 of 32 episodes, clinically diagnosed local infection unassociated with systemic sepsis or skin necrosis was successfully treated without removal of the port using aggressive intravenous and oral antibiotics. Treatment of thrombosis of the catheter with either urokinase or streptokinase infusion was successful in ten of 15 attempts. Seventy-two (22 per cent) of SIP were eventually removed, either after completion of the chemotherapy (20) or because of a complication (52) with 29 SIP being replaced. There was no correlation between the risk of infection or thrombosis and the perioperative use of antibiotics, frequency of SIP use or preoperative white blood cell count, platelet count, coagulation profile, blood urea nitrogen or albumen concentration. SIP provide an excellent method of chronic venous access, having a lower rate of infection and thrombosis in historical comparison with external vascular access devices.

Academic Medical Centers↗
PubMed1987

Effects of hepatic arterial yttrium-90 microsphere administration alone and combined with regional bromodeoxyuridine infusion in dogs.

Brachytherapy by embolization with radiotherapeutic microspheres following intraarterial infusion of a radiosensitizer represents an attempt to combine several selective modalities into a more potent, focused attack on regionally confined tumors. In pursuit of this goal, we examined the ability of foxhounds with surgically implanted hepatic arterial (HA) delivery systems to tolerate a clinically relevant dosage of HA yttrium-90 (Y-90) by microsphere administration either alone or preceded by a 28-day constant HA infusion of either 5-bromo-2'-deoxyuridine (BUDR) or a control solution. Five dogs received BUDR (10 mg/kg/day) and five a control buffer infusion for 28 days immediately prior to the administration of Y-90-coated 15 micron resin microspheres (equivalent of 5000 rads to the entire liver) to each dog on day 31. In all animals, blood counts, bilirubin, amylase, appetite, weight, and behavior remained unchanged. Dogs receiving the microspheres after buffer infusion alone exhibited no hepatic enzyme alanine aminotransferase or alkaline phosphatase elevation. Alanine aminotransferase and alkaline phosphatase levels both rose during the third week of BUDR infusion, and while subsequent microsphere administration further increased enzyme levels, these levels had largely normalized by necropsy on day 82. At necropsy, the type and degree of hepatic toxicity among the animals receiving radioactive microspheres was comparable to that previously described in patients receiving external beam hepatic irradiation at conventional doses (2000-3000 rads). Also noted was a radiation-induced cholecystitis (due in large part to the gallbladder's total reliance on the hepatic artery for blood supply). One resin microsphere dog exhibited a small quantity of microspheres in the lungs causing focal radiation-induced granulomas suggesting the need to assess shunting of microspheres through the liver in clinical studies. Thus, HA Y-90 microspheres with BUDR can produce acceptable, nonlethal, and tolerable toxicities in this dog model suggesting that clinical studies of this combination are not likely to be contraindicated by synergistic toxicity. Although HA BUDR did not contribute significantly to the toxicity of the Y-90 microspheres, HA BUDR by itself administered uninterrupted for 4 weeks may, like HA FUDR (clinically), cause chemical hepatitis/cholangitis. The unexpected fragmentation of the resin spheres (albeit without myelosuppression) has led us to begin studies with a recently developed nondisruptible glass microsphere (ThereSphere) in which the Y-90 is part of the glass matrix and cannot leach.(ABSTRACT TRUNCATED AT 400 WORDS)

Alanine Transaminase↗