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Biomedical subjects

W D Bloomer

Publications and source records attributed to W D Bloomer.

At least 37 records · Page 2Linked to original sources
PubMed1997

Dosimetric analysis and clinical implementation of 6 MV X-ray radiosurgery beam.

The dosimetric data on tissue maximum ratios (TMR), output factors, off axis ratios and beam profiles are presented for small circular fields of diameters ranging from 12.5 to 40 mm for 6 MV radiosurgery beam. It is noticed that dmax increases as the collimator field size increases. Comparison of our data with the published TMR and output factors of similar small circular fields shows that our values are higher than those data. Similarities in trend are noticed with the published isodose volumes for 1-5 and 10 arcs. Not much variation is seen beyond two arcs for 80% isodose volumes for all the field sizes. The variation is small in 20% isodose volumes beyond three arcs. Variations are noticed in 5% isodose volumes for 12.5 mm diameter collimated beam. Our experience has been exclusively with malignant neoplasms. An ideal target volume is covered by 80% isodose volume with 3-4 arcs and a single isocenter. Sixteen patients have been treated to date at our institution, including one patient with brain metastases, two patients with meningiomas, one patient with lymphoma and 12 patients with astrocytomas. The majority of tumors have been treated with single isocenter but some as large as 7 cm have been treated safely with two isocenters.

Brain Neoplasms↗
PubMed1997

Effective atomic numbers of composite materials for total and partial interaction processes for photons, electrons, and protons.

Effective atomic numbers for total and dominant partial interaction processes of photons (1-50 MeV), electrons (1-50 MeV), and protons (1-200 MeV) for the composite materials bone (cortical), muscle (striated), water, polystyrene, Perspex, and Nylon-6 are derived. For photons, the effective atomic number from pair production in the nuclear field is greater than it is from the incoherent scattering. For electrons the effective atomic number from the radiative losses is greater than it is from the collision losses. In both of these cases however, the effective atomic numbers from partial interaction processes remain more or less the same, whereas the number from the total interaction increases with increasing energy. But in the energy regions from 1 to 5 MeV for photons and from 1 to 10 MeV for electrons, the number from the total interaction remains approximately the same for each of these composite materials. For all these materials, in these energy regions the interaction is predominantly with atomic electrons and the contributions from the pair production for photons and radiative losses for electrons are small. In the case of protons the number from total interaction remains more or less the same in the energy region considered. In this energy region collisions with atomic electrons dominate, and the contribution to the total stopping power is mainly from this process only. Hence the derived effective atomic number is basically from the partial process involving the interactions with atomic electrons. Thus, for photons from 1 to 5 MeV for electrons from 1 to 10 MeV and for protons from 1 to 200 MeV, the dosimetric data collected with composite tissue equivalent phantoms, designed on the basis of interaction with atomic electrons for treatment planning, will have less uncertainty.

Biocompatible Materials↗
PubMed1997

9-[3-(2-Nitro-1-imidazolyl)propylamino]-cyclopenteno[b]quinoline hydrochloride (NLCPQ-1): a novel DNA-affinic bioreductive agent as chemosensitizer. I.

9-(3-(2-Nitro-1-imidazolyl)propylamino]-cyclopentano[b]quinoline hydrochloride (NLCPQ-1) is one member of a limited series of 2-nitroimidazole-linked derivatized quinolines we have synthesized to be weak DNA binding compounds. On a concentration basis, NLCPQ-1 is the most potent analogue of the series as a radiosensitizer and cytotoxin of hypoxic cells in vitro and in vivo. This improved efficacy compared to untargeted nitroimidazolic bioreductive compounds has been mainly attributed to its weak DNA binding. In the present study, we investigated the ability of NLCPQ-1 to act synergistically with 4-[bis(2-chloroethyl)amino]-L-phenylalanine (L-PAM, melphalan) or cis-diamminedichloroplatinum (cis-DDP, cisplatin) against tumor cells in vitro and in vivo. We demonstrated that 7 microM NLCPQ-1 potentiated the toxic effect of cis-DDP and L-PAM against V79 cells under hypoxic pretreatment conditions with dose modification factors (DMF) of 2.6 and 2.4, respectively, measured at 0.1 survival. Potentiation was dependent on the concentrations of both the chemotherapeutic agent and NLCPQ-1 as well as on the duration of the hypoxic pretreatment with NLCPQ-1. No potentiation was observed under aerobic cotreatment conditions in vitro. Significant synergism was observed when 15 mg/kg NLCPQ-1 was administered IP at various time intervals before a single dose of L-PAM (5 mg/kg) or cis-DDP (5 mg/kg) in Balb/c mice bearing EMT6 tumors. The in vivo/in vitro assay was used as the investigational endpoint and either the fractional product or isobologramic analysis was used to determine synergistic interactions.

Animals↗
PubMed1996

Effect of radiation on interstitial fluid pressure and oxygenation in a human tumor xenograft.

Elevated interstitial fluid pressure (IFP) is a pathophysiological characteristic of most human and experimental tumors and may be responsible, in part, for the poor distribution of blood-borne therapeutic agents and low blood flow rate in tumors. Recent data in cervical carcinomas in patients suggest that fractionated radiation can lower tumor IFP and increase oxygen partial pressure (pO (2)) in some patients. The goals of this study were to find the minimum dose of radiation required to modulate IFP and pO(2) and to determine the time course of IFP changes due to radiation in a preclinical model. Xenografts of the LS174T human colon adenocarcinoma were grown in the right flank of nude (BALB/c) mice. IFP and pO(2) were measured before and 24 h after graded doses of irradiation. The mean +/- SD initial IFP in untreated tumors was 12.9 +/- 0.5 mm Hg (n=109), and the range was 3.0 to 40.3 mm Hg. The mean +/- SD and median initial pO(2) were 20.2 +/- 2.4 and 11.9 mm Hg, respectively (n=37). IFP and pO(2) were independent of tumor size. Fractionated radiation lowered IFP by 2.5 mm Hg when the total dose was 10 or 15 Gy (P<0.05), but IFP did not change in the controls or the 5-Gy radiation group (P>0.05). Irradiation increased the proportion of tumors at higher oxygen tensions when compared to control tumors. The IFP and tumor volumes were followed for up to 10 days after a single dose of 10, 20, or 30 Gy of irradiation. IFP decreased for all treatment groups. The decrease was most significant for the group receiving 30 Gy. On day five following irradiation, the IFP had decreased by 35%. The changes in IFP and pO(2) occurred before any macroscopic changes in tumor volume could be observed. The radiation-induced decrease in IFP could be, in part, responsible for the increased uptake of monoclonal antibodies following single or fractionated radiation that has been reported in the literature.

Adenocarcinoma↗
PubMed1996

THNLA-1 as radio/chemosensitiser of EMT-6 tumours in mice.

THNLA-1 contains a 2-nitroimidazole tethered to 9-amino-1,2,3,4-tetrahydroacridine. Compared with its parent acridinic analogue, NLA-1, THNLA-1 is a weak DNA-affinic bioreductive compound with a greater mobility along the DNA backbone, decreased aerobic toxicity, greater hypoxic selectivity and a superior in vitro therapeutic index. Also, THNLA-1 behaves as a radio/chemosensitiser in vitro. In this report we have expanded our radio/chemosensitisation studies in vivo, using the EMT-6 mouse mammary tumour model in balb/c mice and the in vivo-in vitro assay. THNLA-1 was given i.p. ( < or = 0.5 ml in saline) at various time intervals before a single dose of 20 Gy whole-body irradiation. Tumours were excised immediately or 24 h after irradiation. Radiosensitisation studies with SR-2508 (i.v.) have been performed in a similar way for comparison purposes. THNLA-1 demonstrated the same radiosensitising effect as SR-2508 but with 19-fold less dose (mmol kg-1). The optimum effect was observed when THNLA-1 was given 1 h before irradiation and the tumours excised 24 h after irradiation. Chemosensitisation studies in the same tumour model and using cis DDP showed that the cytotoxic effect of cis-DDP (5 or 8 mg kg-1, i.p.) was significantly enhanced with 30 or 45 mg kg-1 THNLA-1 given approximately 3 h before cis-DDP. A similar potentiating effect was observed when NLA-1 (27 or 30 mg kg-1) was used, but toxicity was also observed at the higher dose. Limited toxicity studies showed that THNLA-1 is well tolerated up to at least 70 mg kg-1 as a single dose, for more than 40 days.

Animals↗
PubMed1996

9-[3-(2-Nitro-1-imidazolyl)propylamino]-cyclopenteno[b]quinoline hydrochloride (NLCPQ-1). A novel DNA-affinic bioreductive agent as cytotoxin and radiosensitizer.

Our recent studies with 9-[3-(2-nitro-1-imidazolyl)propylamino]-1,2,3,4,-tetrahydroacridine++ + hydrochloride (a 2-nitroimidazole-linked 1,2,3,4-tetrahydroacridine derivative) shows that less effective DNA binding indeed leads to a hypoxic radiosensitizer and cytotoxin of superior in vitro therapeutic index to the fully aromatic nitroimidazole-linked acridine series, which strongly bind to DNA through intercalation. Extending our investigations in this area, we have synthesized and have been evaluating five more nitroimidazoles tethered to quinoline-based chromophores. Here, the in vitro and limited in vivo results of 9-[3-(2-nitro-1-imidazolyl)-propylamino]cyclopenteno[b]quinoline hydrochloride (NLCPQ-1) are presented. On a concentration basis, NLCPQ-1 was the most potent analog so far tested of the above mentioned small series as radiosensitizer or cytotoxin of hypoxic cells. It had a hypoxic selectivity of 9-12 in various cell lines, a C1.6 of approximately equal to 7 microM, and a sensitization enhancement ratio of 3.2 at 50 microM (approximately equal to 27% of the IC50(A)) in V79 cells. Its in vitro therapeutic index (defined as IC50(A)/C1.6) was 25-30 vs. 11 for 9-[3-(2-nitro-1-imidazolyl)propylamino]acridine hydrochloride. The partition coefficient in octanol/water was 0.30 +/- 0.01. The uptake factor (intracellular vs. extracellular concentration) was increased by increasing input concentration and reached 92 at 80 microM. When NLCPQ-1 was administered i.p. at 15 mg/kg, at various time-intervals before a single, 20 Gy radiation dose in Balb/c mice bearing EMT6 tumors, significant synergism was observed. The in vivo-in vitro assay was used as an endpoint, and the fractional product analysis was used to determine synergistic interactions. No toxicity was observed at doses up to 50 mg/kg NLCPQ-1 in nontumor-bearing Balb/c mice.

Animals↗
PubMed1995

Quality assurance for gamma knife stereotactic radiosurgery.

PURPOSE: This quality assurance program is designed for stereotactic radiosurgical units, gamma knife, to check and maintain the unit to preclude accidents and comply with current regulations. MATERIALS AND METHODS: Over 58 stereotactic radiosurgical units using 201 focused 60Co beams have been installed in the last 7 years and are in use at hospitals throughout the world, with at least 11 additional units being prepared to come on-line in the next year. This system has been in use at the University of Pittsburgh Medical Center (UPMC) for 7 years. A comprehensive quality assurance program has been developed. It includes the physics and dosimetry parameters and safety checks required by regulatory agencies. The program, based on over 7 years of experience in measurements, and used during the treatment of over 1500 patients, is separated into three aspects, namely physics, dosimetry, and safety. The UPMC program hopefully will indicate out-of-tolerance problems. Some quality assurance items are checked on a daily basis prior to patient treatment, while other aspects are checked on a weekly, monthly, and/or annual basis. A complete list of items with their respective time tables and tolerances is provided. RESULTS: Although experience shows very small margins of error, larger values were chosen to account for variations in equipment and techniques. CONCLUSIONS: Items included in this quality assurance program should indicate and/or preclude problems encountered in the use of this unit.

Cobalt Radioisotopes↗
PubMed1995

Dosimetric consequences of 10B(n, alpha)7Li reaction occurring at the cellular membrane.

PURPOSE: Microdosimetric expectations of Boron contents are extracted from a CRAY-Monte Carlo simulation of the nuclear reaction 10B(n, alpha)7Li as it occurs on a boronated membrane of a model cell and as the reaction fragments (alpha and Li) traverse into the cellular nucleus. METHODS AND MATERIALS: The present microdosimetry calculation is based upon the assumption that the therapeutic advantage of boron neutron capture therapy (BNCT), while depending upon the RBE and LET of the reaction particles, is equally dependent on the boron carrier preferential localization to tumor tissue, and the boron selectivity to cancerous cells and its specificity within subcellular compartments. In particular, boron fixes to cell membrane as it ought to, using monoclonal antibodies. The present Monte Carlo simulation computes stochastic expectations of alpha/Li energy depositions to the nucleus in a uniformly boronated membrane shell of a spherical cell. Differential energy gain was deduced from the stochastic energy depositions in events of neutron reactions with membrane boron compared against those with natural elements (O, H, N) in the cell. RESULTS: Microdosimetry data are presented in terms of specific energy (keV/micron3) and lineal energy (keV/micron) functions of the nucleus-to-cell volume ratios (NCVR). When folded with the geometric boron content and accounting for background reaction energies, the distributions yield effective energy gain to the cell nucleus per neutron capture event. Boron amount required to yield these energy gains are found to be of the order of picograms of boron per gram of cell mass. CONCLUSION: The boron content as inferred by the present Monte Carlo microdosimetry compares well with that deliverable by present pharmacokinetic means, but are orders of magnitude (mu-grams) less than those deduced previously from anthropomorphic macrodosimetry.

Alpha Particles↗
PubMed1995

Solid phase labeling of monoclonal antibodies with 99mTc using two bifunctional photocleavable reagents.

Two photolabile heterobifunctional O-nitrobenzyl reagents were used to modify B72.3 monoclonal antibody followed by immobilization on a solid support. Antibody was labeled with 99mTc and then cleaved from the resin on irradiation with light of peak intensity at 365 nm. The antibody was restored unmodified after cleavage. The labeled product, void of any impurity or free 99mTc, exhibited compatible imaging quality and biodistribution when compared to the same product labeled using solution chemistry. This new technique offers the potential of a commercially attractive 99Tc-labeling kit. Although the method was designed from the perspective of 99mTc-labeling of monoclonal antibodies, it should be applicable to any solid phase protein modification.

Adenocarcinoma↗
PubMed1994

Gamma-glutamyltranspeptidase expression regulates the growth-inhibitory activity of the anti-tumor prodrug gamma-L-glutaminyl-4-hydroxy-3-iodobenzene.

gamma-L-glutaminyl-4-hydroxy-3-iodobenzene (I-GHB), a novel iodinated analog of gamma-L-glutaminyl-4-hydroxybenzene (GHB), demonstrates greater anti-tumor activity in human and in murine melanoma cell lines. These phenolic amides are substrates for gamma-glutamyltranspeptidase (GGTP; E.C. 2.3.2.2), a cell-membrane-associated ecto-enzyme which is elevated in a number of tumor systems. We now present data to show that the growth-inhibitory activity of I-GHB and GHB may be mediated via GGTP-catalyzed reactions. The growth-inhibitory activity of I-GHB and GHB in pigmented B16-BL6 melanoma cells was blocked significantly by rabbit anti-rat GGTP polyclonal antibodies. The combination of L-serine and sodium borate, a specific transition-state inhibitor of GGTP, as well as acivicin, a glutamine antagonist and irreversible GGTP inhibitor, inhibited the killing of BL6 cells by GHB and I-GHB. To further define the role of GGTP expression in the regulation of phenolic amide cytotoxicity, GGTP-negative Chinese hamster ovary cells (CHO-K1) were transfected with a functional rat renal cDNA representing the full-length GGTP transcript. I-GHB and GHB were significantly more cytotoxic in GGTP cDNA transfected Chinese hamster ovary (CHO-K1-GGTP) cells than in non-transfected CHO-K1 cells. The combination of L-serine and sodium borate blocked the cytotoxic activity of these pro-drugs and also inhibited GGTP-catalyzed formation of polymerized products from these phenolic amides in intact BL6 melanoma and CHO-K1-GGTP cells. Furthermore, melanin formation from GHB was not observed in non-transfected CHO-K1 cells lacking GGTP expression. The combined data strongly suggest that GGTP-catalyzed hydrolysis of the anti-tumor pro-drugs I-GHB and GHB to 4-aminophenols mediates the expression of antitumor activity.

Animals↗
PubMed1994

A novel method for the non-chromatographic purification of technetium-99m-labeled monoclonal antibodies: a study with B72.3 monoclonal antibody.

A cleaning resin has been developed for the non-chromatographic purification of 99mTc-labeled monoclonal antibodies (MAbs). The resin used is a modified form of thiopropylsepharose 6B resin, in which its sulfhydryl groups have been tinylated with stannous chloride. The method requires only simple stirring of the radiolabeling reaction mixture with this tinylated resin and subsequent separation of it from the resin by filtration to obtain a 99mTc-labeled MAb of radiopharmaceutical purity. The method provides an alternative to chromatographic purification of the radiolabeled MAb (i.e. gel filtration or anion exchange chromatography) which has been used in other 99mTc-MAb preparations. For comparison studies, we labeled the B72.3 MAb with NeoRx's diamide dimercaptide chelate radiolabeling kit, split the reaction mixture into two equal portions and then purified one portion with anion exchange chromatography (NeoRx's chosen method) while the other portion was purified with our cleaning resin. Comparison of HPLC chromatograms, percent 99mTc-bound to MAb, biodistribution and scintigraphic results show that our cleaning resin methodology provides a 99mTc-labeled MAb of essentially equal purity and utility as does the established, chromatographic one.

Animals↗
PubMed1994

9-[3-(2-Nitro-1-imidazolyl)propylamino]-1,2,3,4-tetrahydroacridine hydrochloride. A novel DNA-affinic hypoxic cell cytotoxin and radiosensitizer. Comparison with NLA-1.

Electron-affinic compounds with strong DNA intercalating properties have demonstrated less than the expected radiosensitization due to restriction of their mobility along the DNA backbone and their lower extravascular diffusion in tumors. A 2-nitroimidazole linked 1,2,3,4-tetrahydroacridine derivative (THNLA-1) has been synthesized as a hypoxia-selective cytotoxin and radiosensitizer with presumably lower DNA-binding affinity due to the perturbation of the planarity in the acridine ring. THNLA-1 is a good hypoxia-selective cytotoxin with a differential toxicity of approximately equal to 11 in V79 cells, but it is approximately equal to 2 times less potent on a concentration basis than NLA-1 (the 2-nitroimidazole linked acridine analog). However, THNLA-1 is a very efficient radiosensitizer, showing a sensitization enhancement ratio (SER) of 3.04 +/- 0.05 at 100 microM at 25 degrees C, and the concentration giving an SER of 1.6(C1.6) is 19.0 +/- 0.5 microM. The therapeutic index, defined as the ratio of the clonogenic IC50 under aerobic conditions for 1-h exposure (IC50A,1h) to the C1.6 value, is 20 for THNLA-1 vs. 11 for NLA-1. THNLA-1's partition coefficient in octanol/water is 0.14 +/- 0.02. Topoisomerase I and II interaction studies with THNLA-1 showed that topoisomerase I-mediated relaxation of supercoiled DNA was inhibited at relatively high THNLA-1 concentrations (> or = 1000 microM), while topoisomerase II-mediated decatenation of kinetoplast DNA remained unaffected even in concentrations toxic in vitro under aerobic conditions. Uptake studies under aerobic conditions showed high intracellular drug concentrations, compatible with the required ones for topoisomerase I inhibition.

Aerobiosis↗
PubMed1993

Mechanism(s) regulating inhibition of thymidylate synthase and growth by gamma-L-glutaminyl-4-hydroxy-3-iodobenzene, a novel melanin precursor, in melanogenic melanoma cells.

A proposed mechanism for the melanoma specific activity of phenolic amines is based upon the ability of the enzyme tyrosinase to oxidize these prodrugs to toxic intermediates. In this study, we synthesized an iodinated analog of gamma-L-glutaminyl-4-hydroxybenzene (GHB) with increased antimelanoma activity in both human and murine melanoma cell lines. GHB and gamma-L-glutaminyl-4-hydroxy-3-iodobenzene (I-GHB) were shown to be substrates for both mammalian and mushroom tyrosinase. Glutathione, a cellular antioxidant, inhibited tyrosinase mediated formation of gamma-L-glutaminyl-3,4-benzoquinone (GBQ) from GHB, inhibited melanin production, and blocked the inhibition of the enzyme thymidylate synthase by oxidized GHB. Buthionine sulfoximine (BSO) depletion of cellular glutathione enhanced the growth inhibitory activity and the inhibition of in situ thymidylate synthase by phenolic amines in melanoma cells. GHB and I-GHB were shown to be approximately 5- and 10-fold more cytotoxic, respectively, in highly metastatic B16-BL6 cells than in weakly metastatic B16-F1 cells with approximately equal tyrosinase activity. B16-BL6 cells had approximately 20-fold higher gamma-glutamyltranspeptidase (gamma-GTPase) activity than B16-F1 cells which suggested the possible involvement of this enzyme in the activation of the cytotoxicity of the phenolic amines. 4-Aminophenol, a product of gamma-GTPase reaction with GHB, was a substrate for tyrosinase and a potent inhibitor of in situ thymidylate synthase activity in melanogenic cells. In pigmented melanoma cells containing the enzyme tyrosinase, the quinone mediated mechanism of phenolic amine cytotoxicity may be uniquely important and the cellular antioxidant glutathione essential in the detoxification of these quinone-generated intermediates.

Animals↗
PubMed1993

Enhancement of pulmonary metastasis formation and gamma-glutamyltranspeptidase activity in B16 melanoma induced by differentiation in vitro.

B16 melanoma sublines (B16-F10-BL6 and B16-F1) exhibited elevated adenosine 3',5'-cyclic monophosphate (cAMP) levels when cultured in Dulbecco's modified Eagle's medium (DMEM) in comparison to cells in RPMI-1640 medium. In parallel, cells cultured in DMEM had increased tyrosinase activity, melanization and dendrite formation, all markers of melanoma differentiation. Also, the proliferative rates of both cell lines were decreased by 80-85% when cultured in DMEM relative to cells maintained in RPMI-1640 medium. In these studies, elevated levels of the melanin precursors tyrosine (Tyr) and phenylalanine (Phe) found in DMEM were shown not to be solely responsible for the phenotypic changes observed with DMEM. Both BL6 and B16-F1 cell lines formed more experimental pulmonary tumor metastasis in syngeneic C57BL/6 mice when maintained in DMEM vs RPMI-1640 medium. Analysis of metastasis formation in nude mice with normal and depleted natural killer (NK) cell activity revealed that the enhanced lung colonizing capacity of the BL6 cells maintained in DMEM was independent of the function of T-cell or NK-cell-mediated immunity. A close association between metastatic ability of tested lines and the expression of the membrane-associated enzyme gamma-glutamyltranspeptidase (gamma-GTPase, EC 2.3.2.2) was observed. The highly metastatic BL6 cell line had 20-fold higher levels of gamma-GTPase activity than the weakly metastatic B16-F1 cell line. Both cell lines, when grown in DMEM, had elevated gamma-GTPase activity that paralleled augmentation of metastatic ability. The dramatic changes in lung-colonizing capacity of the variant B16 melanoma cells maintained in DMEM in contrast to those grown in RPMI-1640 medium may serve as a useful model in understanding certain steps involved in triggering cell differentiation as well as metastasis development.

Animals↗
PubMed1993

A technique to prepare boronated B72.3 monoclonal antibody for boron neutron capture therapy.

B72.3 monoclonal antibody has been successfully boronated using mercaptoundecahydro-closo-dodecaborate (boron cage compound). The reagent was incorporated by first reacting the lysine residues of the antibody with m-maleimidobenzoyl succinimide ester (MBS), followed by Michael addition to the maleimido group by the mercapto boron cage compound to form a physiologically stable thioether linkage. Boron content of the antibody was determined by atomic absorption spectroscopy. For biodistribution studies, boronated antibody was radioiodinated with idogen. 125I-labeled and boronated B72.3 monoclonal antibody demonstrated clear tumor localization when administered via tail vein injections to athymic nude mice bearing LS174-T tumor xenografts. Boronated antibody was calculated to deliver 10(6) boron atoms per tumor cell. Although this falls short of the specific boron content originally proposed as necessary for boron neutron capture therapy (BNCT), recent calculations suggest that far fewer atoms of 10B per tumor cell would be necessary to effect successful BNCT when the boron is targeted to the tumor cell membrane.

Adenocarcinoma↗