Search PubMed⌕ Search

Biomedical subjects

W D Bloomer

Publications and source records attributed to W D Bloomer.

At least 55 records · Page 3Linked to original sources
PubMed1993

A new method of technetium-99m labeling of monoclonal antibodies through sugar residues. A study with TAG-72 specific CC-49 antibody.

We have developed a very efficient labeling technique for monoclonal antibodies with technetium-99m. Oxidation of sugar residues on the IgG class of antibodies leads to the generation of aldehyde groups which are further reacted with two newly developed hydrazide compounds. This methodology introduces sulfhydryl groups on the antibody through sugar residues which can be labeled with technetium-99m. We have studied the TAG-72 specific second generation antibody CC-49. The specific activity of the labeled antibody was high without loss of its immunoreactivity.

Adenocarcinoma↗
PubMed1993

2-Alkylsulfonyloxy-3-hydroxy-1,4-naphthoquinones: a novel class of radio- and chemosensitizers of V79 cells.

Four 2-alkysulfonyloxy-3-hydroxy-1,4-naphthoquinone derivatives, VH(1-4), have been synthesized as a novel class of bioreductive alkylating agents and tested as hypoxic cytotoxins, radiosensitizers, and chemosensitizers of V79 cells. In this series, the naphthoquinone is the bioreductive moiety while the sulfonyloxy group, as a good leaving group, could lead to alkylations of nucleophilic substrates in the cells. All VH-compounds are moderately selective cytotoxins of V79 cells with a differential aerobic-hypoxic toxicity of approximately 2, i.e. ratio of drug concentrations to give 50% killing for aerobic versus hypoxic cells. All derivatives are radiosensitizers of hypoxic V79 cells but only VH-3 can give a sensitization enhancement ratio of 2.05 at a nontoxic concentration. Finally, all VH-derivatives are good chemosensitizers of V79 cells to the aerobic toxicity of melphalan, either under hypoxic preincubation without melphalan or under aerobic coincubation with melphalan. The dose modification factors were approximately 2, at low, non-toxic concentrations.

Absorption↗
PubMed1992

Effects of tyrosinase activity on the cytotoxicity of 4-S-cysteaminylphenol and N-acetyl-4-S-cysteaminylphenol in melanoma cells.

The rationale for melanoma specific antitumor agents containing phenolic amines is based in part upon the ability of the enzyme tyrosinase to oxidize these prodrugs to toxic intermediates. Two phenolic amine compounds, N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) and 4-S-cysteaminylphenol (4-S-CAP), demonstrated growth inhibitory activity with a variety of melanoma cell lines and were essentially non-toxic to non-melanoma cell lines. Theophylline, an inhibitor of cyclic nucleotide phosphodiesterase, increased in situ tyrosinase activity and enhanced the antimelanoma effects of 4-S-CAP and N-Ac-4-S-CAP in pigmented melanoma cell lines. Phenylthiourea, a specific inhibitor of tyrosinase activity, partially blocked the growth inhibitory activity of N-Ac-4-S-CAP in human pigmented melanoma cells. Buthionine sulfoximine, an inhibitor of the synthesis of the cellular antioxidant glutathione, potentiated the growth inhibitory activity of N-Ac-4-S-CAP in pigmented melanoma cells.

Antineoplastic Agents↗
PubMed1992

Thymidylate synthase as a target enzyme for the melanoma-specific toxicity of 4-S-cysteaminylphenol and N-acetyl-4-S-cysteaminylphenol.

The rationale for melanoma-specific antitumor agents containing phenolic amines is based in part on the ability of the enzyme tyrosinase to oxidize these prodrugs to toxic intermediates. The phenolic amine compounds 4-S-cysteaminylphenol (4-S-CAP) and N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) inhibited in situ thymidylate synthase activity in pigmented melanoma cell lines but had little or no effect on nonpigmented and nonmelanoma cell lines. Theophylline, a cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor, increased tyrosinase activity and potentiated the inhibition of in situ thymidylate synthase by N-Ac-4-S-CAP. The inhibition of in situ thymidylate synthase by both drugs in pigmented melanoma cells correlated with the inhibition of DNA synthesis and cell growth and was not due to an indirect effect caused by inhibition of the enzyme dihydrofolate reductase. 4-S-CAP inhibition of thymidylate synthase activity in cell free extracts required oxidation of the drug. In the presence of tyrosinase, the concentration causing a 50% inhibition of thymidylate synthase activity (IC50) in cell-free extracts was less than 10 microM, but no inhibition was observed in its absence, even at a drug concentration of 500 microM. Two reducing agents, dithioerythritol and glutathione, effectively blocked the inhibition of thymidylate synthase by oxidized 4-S-CAP. In pigmented melanoma cells containing the enzyme tyrosinase, the quinone-mediated mechanism of inhibition of DNA synthesis via inhibition of thymidylate synthase may be uniquely important in the expression of phenolic amine cytotoxicity.

Antineoplastic Agents↗
PubMed1992

Radiosensitization and hypoxic cell toxicity of NLA-1 and NLA-2, two new bioreductive compounds.

Two new bioreductive compounds, 9-[3-(2-nitro-1-imidazolyl)propylamino]acridine hydrochloride (NLA-1) and 9-[2-(2-nitro-1-imidazolyl)ethylamino]acridine hydrochloride (NLA-2), have been prepared. They feature an acridine ring to intercalate with DNA, a 2-nitroimidazole ring as the radiosensitizing moiety and an amino functionality for increased DNA-binding and hydrophilicity. Time and concentration dependent cytotoxicity as well as radiosensitization efficacy of the two compounds under hypoxic or aerobic conditions were determined in vitro using V-79 cells and an MTT colorimetric or clonogenic assay. The isosensitization point (ISP), defined as that drug concentration which results in the same survival decrement upon exposure of hypoxic or oxygenated cells to a given radiation dose, has been determined for both compounds at 7.5 Gy and the values are significantly lower than the ISPs of 5-[3-(2-nitro-1-imidazolyl)propyl]phenanthridinium bromide, 2-(2-nitro-1-imidazolyl)ethylamine or misonidazole (MISO). NLA-1 and NLA-2 are potent hypoxic cytotoxins and on a concentration basis, more potent than MISO as radiosensitizers in vitro. The sensitization enhancement ratios were significantly increased when 1 h drug preincubation under hypoxia at 37 degrees C was applied, before irradiation at room temperature.

Aminoacridines↗
PubMed1992

Potentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea's toxicity in vitro by two new bioreductive agents.

Two new bioreductive compounds, 9-[3-(2-nitro-1-imidazolyl)propylamino]acridine hydrochloride (NLA-1) and 9-[2-(2-nitro-1-imidazolyl)ethylamino]acridine hydrochloride (NLA-2), which behave as hypoxic cytotoxins and radiosensitizers, have been investigated for potentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea's (CCNU) cytotoxic activity in vitro using V-79 cells. The preincubation effect as well as conditions of coadministration of CCNU with each sensitizer have been examined. In this latter case, the median-effect analysis was applied to evaluate whether the phenomenon was additive or synergistic. A clonogenic assay was used to score survival. Both bioreductive compounds, even at very low concentrations, significantly enhance the cytotoxic activity of CCNU under conditions of hypoxic preincubation. The enhancement of CCNU cytotoxicity is dependent upon preincubation time and the concentrations of both CCNU and the specific bioreductive agent. Coincubation of cells under hypoxia with CCNU and each bioreductive agent led to some potentiation, but only at lower survival levels. No chemosensitization was observed under aerobic conditions with either sensitizer.

Aminoacridines↗
PubMed1991

Interstitial hypertension in carcinoma of uterine cervix in patients: possible correlation with tumor oxygenation and radiation response.

Elevated tumor interstitial fluid pressure (IFP) is believed to be responsible, at least in part, for the poor penetration and heterogeneous distribution of blood-borne therapeutic agents and nutrients in solid tumors. Using the wick-in-needle technique, IFP was measured in human patients with squamous cell carcinoma of the uterine cervix at the initial and final stages of fractionated external beam radiotherapy. Mean IFP values ranged from 10 to 26 mm Hg with an overall mean of 15.7 +/- 5.7 (SD) mm Hg in stage IIB and IIIB tumors (n = 12) and from 0 to 3 mm Hg in normal cervix (n = 3). IFP decreased in some patients with therapy while in others it increased. The changes in IFP values agree well with the clinical response to radiotherapy (n = 7, P less than 0.05). Oxygen tension, measured in selected tumors (n = 3) with polarographic oxygen microelectrodes, inversely correlated with IFP. These results show for the first time that the IFP in human cervical carcinomas is elevated, and that it can be lowered in some tumors using fractionated radiation therapy. These findings also suggest that IFP values may provide an indication of tumor oxygenation and that IFP modifications could be prognostic indicators of radiation response.

Adult↗
PubMed1991

Radiotoxicity of 17 alpha-[125I]iodovinyl-11 beta-methoxyestradiol in MCF-7 human breast cancer cells.

Therapeutic strategies for human breast cancer using 125I-labeled steroid hormones are clinically attractive in light of the estrogen dependence of many human breast cancers and the favorable microdosimetry resulting from 125I decay. We determined the uptake specific estrogen receptor binding and radiotoxicity of 17 alpha-[125I]iodovinyl-11 beta-methoxyestradiol (125IVME2) in vitro using cultured MCF-7 human breast carcinoma cells. 125IVME2 rapidly enters MCF-7 cells and reaches a plateau in the presence of competing 10(-7) M 17 beta-estradiol. In the absence of competitor, uptake is substantially greater before reaching a plateau. Efflux of 125IVME2 from cells incubated in the absence of estradiol decreases to levels corresponding to specific binding. Under equilibrium conditions and in the absence of competitor, 125IVME2 binds to both specific and nonspecific sites but, in the presence of excess 17 beta-estradiol, the observed binding is nonspecific. 125IVME2 is cytotoxic to exponentially growing MCF-7 cells and produces a survival curve typical of those observed for [125I]iododeoxyuridine and 16 alpha-[125I]iodoestradiol.

Binding, Competitive↗
PubMed1990

Clinical use of a wing field with transmission block for the treatment of the pelvis including the inguinal node.

Treatment planning of photon and electron beams to include the pelvis and the groin poses a technical difficulty of positioning beams, and a dosimetric problem of abutting fields at the groin. We have analyzed a simpler AP/PA method using a central transmission block. The posterior portal is smaller and opposes only the pelvic portion of the anterior portal under the transmission block, while the anterior extended portion (hence the wing) is unattenuated to treat the inguinal region. By calculating the attenuation thickness according to the patient's separation and the beam quality, the dose distribution is tailored to yield the proper dose to the pelvic mid-plane and the inguinal nodes while minimizing the dose to the femora. Measured dose distribution (6MV) using film dosimetry in a tissue-equivalent phantom indicates that a 30% hot spot is created by the posterior portal diverging into the wings of the anterior field. Therefore, the pelvic attenuator is tapered at its lateral edges, thereby significantly reduced the dose inhomogeneity (5%) at the groin. Clinical methods are outlined for the verification of the patient portal films against possible mismatch in beam divergence.

Groin↗
PubMed1990

Physics of gamma knife approach on convergent beams in stereotactic radiosurgery.

The Presbyterian-University Hospital of Pittsburgh installed the first clinically designated Leksell gamma knife in the U.S. in August 1987. Gamma knife radiosurgery involves stereotactic target localization with the Leksell frame and subsequent closed-skull single-treatment session irradiation of a lesion with multiple highly focused gamma ray beams produced from 60Co sources. The hemispherical array of sources, the large number of small-diameter beams, and the steep dose gradients surrounding a targeted lesion make physical characterization of the radiation field complex. This paper describes the physical features and the operation of the gamma knife as well as the calibration procedures of the very small, well-collimated beams. The results of studies using in-phantom ion chamber, diode, film, and lithium fluoride thermoluminescent dosimetry were all in close agreement. Both single-beam and multiple-beam dose profiles were measured and reported for the interchangeable helmets, which have 4-, 8-, 14-, and 18-mm-diameter collimators. We also describe the dose calculation and treatment planning algorithm in the treatment planning system. Measurements of the accuracy of mechanical and radiation alignment are also performed and discussed.

Brain Diseases↗
PubMed1989

Cytotoxicity of receptor-mediated 16 alpha-[125I]iodoestradiol in cultured MCF-7 human breast cancer cells.

Therapeutic strategies using 125I-labeled steroid hormones are attractive in light of the estrogen dependence of many human breast cancers and the favorable microdosimetry resulting from 125I decay. We determined the uptake, specific estrogen receptor (ER) binding, and cytotoxicity of 16 alpha-[125I]iodoestradiol in cultured MCF-7 human breast cancer cells. The cytotoxicity of receptor-mediated 125I appears to be sufficient in MCF-7 cells to warrant in vivo experimentation. Furthermore, cytotoxicity not specific to ERs is minimal within the dose range necessary for ER saturation and specific cell killing. Competitive toxicity studies using nonradioactive 17 beta-estradiol demonstrate an unequivocal relationship between ER binding and clonogenic viability.

Animals↗
PubMed1989

Diminished corticosterone levels in nude mice implanted with MCF-7 or ZR-75-1 human breast tumor cells.

Corticosteroid levels were studied in the plasma of athymic mice implanted with human breast tumor cells, either from MCF-7 or ZR-75-1 cell lines. There was a highly significant decrease in plasma corticosterone levels in the mice implanted with these tumor cells. There was no significant effect on corticosterone of GW 39 colon cancer cells, LS 174T colon cancer cells, or Calu-3 lung cancer cells.

Animals↗
PubMed1989

[125I]iodotamoxifen cytotoxicity in cultured human (MCF-7) breast cancer cells.

We evaluated the uptake and radiotoxicity of [125I]iodotamoxifen (125ITAM) in MCF-7 human breast cancer cells in the presence or absence of excess non-radioactive estradiol (E2) or iodotamoxifen (ITAM). Studies in cells under wash-out conditions and in nuclei isolated from previously exposed cells showed that 125ITAM binds estrogen receptor (ER) and antiestrogen binding sites (AEBS) and has the capacity for considerable non-specific binding. The radiotoxicity of 125ITAM was a complex function related to ER content and/or function as well as interactions with ER, AEBS and non-specific binding. Addition of E2 or ITAM abolished ER mediated cell killing. ITAM but not E2 abolished AEBS mediated cytotoxicity. Non-specific binding accounted for considerable cytotoxicity. Although these studies confirm the radiotoxicity of nuclear bound 125I, multiple nuclear binding sites, variability in ER content and function and non-specific binding will all adversely influence ultimate clinical efficacy.

Breast Neoplasms↗
PubMed1989

Activity of pp60c-src protein kinase in human breast cancer.

Because there is elevation of pp60c-src activity in breast carcinoma tissue, we analyzed primary breast cancer tissue samples from 30 women to determine whether pp60c-src activity correlated with specific clinical parameters. We found that tumors with a progesterone receptor had higher pp60c-src activity than tumors without such a receptor. But there was no association of pp60c-src activity with the presence of an estrogen receptor or of nodes, or with menopausal status or age. The function of pp60c-src in normal cells and in breast cancer is unknown, as is the significance of our finding of an association of elevated pp60c-src activity and the presence of progesterone receptors.

Adult↗
PubMed1988

Preliminary observations of malignant melanoma therapy using radiolabeled alpha-methyltyrosine.

A strategy for cancer therapy using astatine-211-labeled alpha-methyltyrosine (211At-AMT) was studied in cultured B16 melanoma cells and compared to the radiotoxicity of iodine-125-labeled iododeoxyuridine (125IUdR), a thymidine analogue. Both 125I and 211At deliver lethal doses of irradiation to melanoma cells when administered as 125IUdR and 211At-AMT. The alpha decay of astatine-211 is more effective however, needing only a fraction of the cellular radioactivity of 125IUdR to effect comparable clonogenic survival. Compared with 125IUdR, 125I-AMT is not cytotoxic because the range of the low energy electrons released does not interact with DNA. Uptake of radiolabeled AMT by melanotic cells is enhanced by theophylline. This preliminary evidence suggests that 211At-labeled melanin precursors may be exquisitely cytotoxic to B16 melanoma cells.

Astatine↗