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Biomedical subjects

W D Bloomer

Publications and source records attributed to W D Bloomer.

105 records · Page 6Linked to original sources
PubMed1978

5-(125I)-iododeoxyuridine and the Auger effect: biological consequences and implications for therapy.

If the full potential for the use of radionuclides in the treatment of cancer is to be realized, the problem of locating internal emitters with a short range of action in the sensitive targets of the cell must be solved. It is already clear that only two types of radioactivity will satisfy these requirements: alpha decay and, as this review has attempted to demonstrate, electron capture with subsequent Auger cascade. Although mechanisms have yet to be clarified, it is clear that an Auger emitter located within the genetic apparatus is extremely radiotoxic with as little as a single disintegration being lethal in some organisms. Moreover, the available experimental evidence suggests that the extreme lethality is confined to a very small volume, probably that of molecular dimensions. These facts highlight the advantages as well as the limitations of using the Auger effect for cancer therapy. A favorable feature is that extreme damage is confined only to the cell in which radioactive decay takes place; a disadvantage is that the biochemical specificities are very great. Not only must the radioactivity be directed specifically to malignant calls, but it must also be very closely approximated to their genetic structures as well. This circumstance has its counterpart in considering the use of electron capture emitters for diagnostic purposes since their potential hazard depends in large measure on their cellular localization. These microscopic considerations have largely been neglected in traditional radionuclide dosimetry but, considering the magnitude of the effect and the widespread use of such radionuclides as chromium-51, gallium-67, selenium-75, iodine-123, and thallium-201, they should be reexamined. In some cases, such as with 67Ga, we may find that standard dosimetric calculations have overestimated the hazard. In others, the opposite may be true. Whichever the result, it should serve as an impetus to obtain data on the cellular localization of commonly employed radionuclides and on the microscopic distribution of dose. Lastly, it is clear that Auger emitters can be used as ultramicroscopic probes to define the radiosensitive targets of the cell and to destroy regions of subcellular dimensions. This potential use in radiation and cellular biology has only now begun to be exploited.

Animals↗
PubMed1978

Therapeutic application of iodine-125 labeled iododeoxyuridine in an early ascites tumour model.

In its decay, iodine-125 emits cascades of Auger electrons with subcellular ranges and leaves a highly charged tellurium-125 product. When iodine-125 is incorporated into DNA as the thymidine analog 125I-UdR, the localized deposition of such energy has been shown to be extremely radiotoxic. This report presents the results of quantitative investigations into the therapeutic efficacy of 125I-UdR in an early ascites murine tumour model. An ovarian embryonal cell carcinoma has been maintained by serial intraperitoneal transplantation. Challenge doses of 10(4)-10(6) cells were used. Four divided doses of 125I-UdR were administered starting 24 h after tumour cell inoculation; the interval between doses was 4 or 12 h. Therapeutic efficacy was demonstrated by prolonged median and increased absolute survivals of treated animals. Divided doses were more effective than single doses, and antineoplastic activity was related to fractionation. The degree of cell killing with a given fractionation scheme was constant over the range of 10(4)-10(6) cells, and total doses of 50-100 muCi resulted in a 2-3 log killing of tumour cells (1-0.1% cell survival). Therapy with 125I-UdR affords a promising new approach to the treatment of cancer. The therapeutic potential of iodine-125 and other radionuclides whose decay results in a highly localized deposition of energy merits further investigation.

Animals↗
PubMed1976

Mammography of the definitively irradiated breast.

The role of mammography in evaluating tumor response was examined in 27 patients undergoing definitive radiation therapy for breast cancer. Radiographic changes observed after treatment included progressive skin thickening, fibrosis of the subcutaneous tissue, and breast retraction. The persistence of a mass more than six months after irradiation suggests treatment failure. Serial mammography may be particularly important in the evaluation of patients with locally advanced disease who require extensive radiation therapy and in whom physical examination is inadequate for the assessment of tumor response.

Breast Neoplasms↗
PubMed1976

Carcinoembryonic antigen (CEA) monitoring of radiation therapy for colorectal cancer.

Serial CEA radioimmunoassays were performed on 16 patients receiving preoperative radiation therapy of rectal cancer or irradiation of recurrent or metastatic colorectal cancer. Radiation therapy of localized colorectal cancer reliably reduced previously elevated circulating CEA titers. Significant decrease of elevated CEA titers with accumulating doses of irradiation may indicate that the bulk of CEA-producing tumor is within the radiation treatment portal and assist in patient management decisions. The decrease of circulating CEA with preoperative radiation therapy was of short duration and may indicate that surgical resection should not be delayed more than 6-8 weeks after irradiation. Because of the high frequency of false positive and false negative results, CEA must be used only in conjunction with other clinical and laboratory parameters.

Carcinoembryonic Antigen↗
PubMed1975

Radionuclide immunoglobulin lymphangiography: a case report.

Iodine-131-labeled immunospecific gamma globulin derived from immunization of rabbits with F antigen, a tumor associated antogen in Hodgkin's disease, has been utilized for intralymphatic infusion in a patient with known recurrent Hodgkin's disease inthe inguinofemoral and pelvic regions. Rectilinear scanning successfully delineatedthe tumor masses, and external monitoring showed retention of activity in the tumor sitesover an 8-day period.

Adult↗
PubMed1966

Bipiperidyl mustard, a new obesifying agent in the mouse.

Bipiperidyl mustard, after conversion to its bis-cyclic immonium ion forme, has been found to cause rapid and extensive lipid deposition in mice given single doses of the drug. The obe sity appears to result from an alkylation reaction; the responses of the treated ani mals to food restriction and realimenta tion resemble those observed in gold thioglucose-treated mice; also in anal ogy to gold thioglucose, the bipiperidyl mustard effects can be counteracted by sulfhydryl compounds. These observa tions are suggestive of a similarity of mode of action between the alkylating agent and gold thioglucose, a conclusion which is supported by preliminary find ings of ventromedial lesions in the hypo thalamus of the bipiperidyl mustard treated mice.

Acetylcysteine↗
PubMedDate not supplied

Effect of prior radiotherapy on postsurgical wound infection.

Radiotherapy causes both epithelial and endothelial damage acutely with the subsequent development of interstitial and perivascular fibrosis. These effects may lead to decreased blood flow, delayed wound healing, and a delay in achieving normal wound tensile strength. In a retrospective study of wound infections that developed in 23 of 354 patients (6%) accrued in a series of prospective, randomized antibiotic trials, the incidence of wound infection in patients receiving prior radiotherapy (7.6%) was not statistically different from the incidence of wound infection observed in patients who had had no prior radiotherapy (6.3%). Wound infection that developed in patients after radiotherapy tended to be associated with increased hospitalization, an increased rate of fistulization, and more frequently required secondary surgical repair. It is concluded that major head and neck procedures can be accomplished without an absolute increase in the incidence of wound infection. However, when postoperative complications occur, it may result in a significant increase in morbidity.

Double-Blind Method↗
PubMedDate not supplied

In vitro evaluation of 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-trifluoromethylquinoline hydrochloride (NLTQ-1), a new bioreductive agent as a hypoxia marker by 19F-magnetic resonance spectroscopy (19F-MRS).

19F-labeled bioreductive drugs bound to hypoxic cells in tumors could be detected by nuclear magnetic resonance, provided that they do not lose 19F during their metabolism. NLTQ-1, a 2-nitroimidazole-linked 7-trifluoromethylquinoline, has been synthesized to furnish this aim. NLTQ-1 demonstrated hypoxic selectivities of 7-10 in various cell-lines, in vitro. Uptake studies in V79 cells showed a 5 to 6 fold greater intracellular than extracellular concentration at a range of 100-300 microM input concentrations. A strong sharp peak, which was identified as the parent compound, was observed in the 19F-NMR spectrum of 90% MeCN extracts of V79 cells aerobically exposed to NLTQ-1, indicating that NLTQ-1 was not metabolized under aerobic conditions. Similarly, 19F NMR efflux studies in intact cells showed that the NLTQ-1 was bound to the cells predominantly under hypoxic conditions. 19F-NMR spectra of intact cells, exposed under hypoxic conditions to NLTQ-1, and of their lysates, after precipitation of various cellular components, indicated that possible covalent binding of NLTQ-1 had occurred with macromolecules such as proteins and nucleic acids. Therefore, NLTQ-1 might be suitable as a 19F-MRS/MRI hypoxia probe, although further in vivo work is necessary to verify this matter.

Aerobiosis↗
PubMedDate not supplied

Intra-articular radiation synovectomy.

Fifty-three knees in 44 patients with severe, chronic rheumatoid arthritis (RA) were treated by the instillation of an intra-articular radionuclide (dysprosium-165; 165Dy) coupled with a large, relatively inert carrier (ferric hydroxide macroaggregate). The extremely low leakage rates found in earlier animal experiments were confirmed in the human, with a mean leakage rate of 0.3% of the injected dose. This leakage corresponds to a total body dose of 0.4 rad and a liver dose of 2.5 rad, equivalent to a lumbosacral series of diagnostic radiographs. Eighty percent of the treated knees showed improvement, which was maintained as long as one year after treatment. There was a direct correlation between the preoperative radiographic stage and the response to treatment, with patients in Stages I and II more likely to have a good or excellent response at one year. There was also good correlation between clinical improvement and improvement in technetium-99m (99mTc)-pertechnetate flow scintigraphy. Chemical synovectomy by the instillation of appropriate radionuclides can be recommended as an effective means of reducing inflammation, effusion, and pain in patients with RA. The duration of favorable results cannot be predicted, but the results to date suggest that longevity should be comparable with that of surgical synovectomy. Like surgical synovectomy, radiation synovectomy is most effective in the early stages of the disease process, before there is extensive destruction of cartilage and bone.

Adolescent↗
PubMedDate not supplied

THNLA-1: a DNA-targeted bioreductive agent as chemosensitizer in vitro and in vivo.

THNLA-1 is a recently synthesized 2-nitroimidazole based, DNA-affinic bioreductive agent. It features a tetrahydroacridinic chromophore, which allows loose binding to DNA and therefore greater mobility along its backbone. THNLA-1 was proved to be a very good radiosensitizer and cytotoxin of hypoxic cells in vitro with an improved therapeutic index compared to the fully aromatic analog NLA-1. In this report we investigated the interaction of THNLA-1 with cis-DDP or L-PAM in the sensitive V79 and resistant OVCAR cells, using various schedule protocols. Also, the THNLA-1/cis-DDP interaction in balb/c mice has been investigated, using the EMT-6 mouse tumors. Isobologramic as well as fractional product concept analysis, clearly showed that synergistic interaction occurs between THNLA-1 and each chemotherapeutic agent, under hypoxic pretreatment conditions of the cells with THNLA-1 in vitro. The dose modification factor (DMF) values obtained in the resistant OVCAR-3 cells are similar to those obtained for the approximately 4 times more sensitive V79 cells. Therefore, the DMF value for e.g. L-PAM at 0.1 survival fraction, is approximately 2.76 when 15 microM THNLA-1 was used in OVCAR-3 cells, and approximately 2.50, when 10 microM THNLA-1 was used in V79. The supra-additive effect is dependent on the hypoxia-pretreatment time with THNLA-1, on THNLA-1 concentration and on the concentration of the chemotherapeutic drug. The limited in vivo study showed that THNLA-1, at doses significantly lower than its MTD, strongly potentiates the killing effect of cis-DDP and that the optimum effect during the combination treatment was observed when THNLA-1 was administered i.p., 2.5-3.0 h before cis-DDP. Toxicity studies in balb/c mice (without tumors) showed that THNLA-1 is well tolerated up to at least 70 mg/kg for more than 40 days while no toxicity was observed with the combined drugs used in our experimental protocol. These results are promising for the potential clinical use of THNLA-1 as an adjuvant in chemotherapy.

Animals↗