Biomedical subjects

D S Gridley

Publications and source records attributed to D S Gridley.

62 records · Page 4Linked to original sources

PubMedDate not supplied

Dose and dose rate effects of whole-body gamma-irradiation: I. Lymphocytes and lymphoid organs.

The major goal of part I of this study was to compare varying doses and dose rates of whole-body gamma-radiation on lymphoid cells and organs. C57BL/6 mice (n = 75) were exposed to 0, 0.5, 1.5, and 3.0 Gy gamma-rays (60Co) at 1 cGy/min (low-dose rate, LDR) and 80 cGy/min (high-dose rate, HDR) and euthanized 4 days later. A significant dose-dependent loss of spleen mass was observed with both LDR and HDR irradiation; for the thymus this was true only with HDR. Decreasing leukocyte and lymphocyte numbers occurred with increasing dose in blood and spleen at both dose rates. The numbers (not percentages) of CD3+ T lymphocytes decreased in the blood in a dose-dependent manner at both HDR and LDR. Splenic T cell counts decreased with dose only in HDR groups; percentages increased with dose at both dose rates. Dose-dependent decreases occurred in CD4+ T helper and CD8+ T cytotoxic cell counts at HDR and LDR. In the blood the percentages of CD4+ cells increased with increasing dose at both dose rates, whereas in the spleen the counts decreased only in the HDR groups. The percentages of the CD8+ population remained stable in both blood and spleen. CD19+ B cell counts and percentages in both compartments declined markedly with increasing HDR and LDR radiation. NK1.1+ natural killer cell numbers and proportions remained relatively stable. Overall, these data indicate that the observed changes were highly dependent on the dose, but not dose rate, and that cells in the spleen are more affected by dose rate than those in blood. The results also suggest that the response of lymphocytes in different body compartments may be variable.

Animals↗

PubMedDate not supplied

Dose and dose rate effects of whole-body gamma-irradiation: II. Hematological variables and cytokines.

The goal of part II of this study was to evaluate the effects of gamma-radiation on circulating blood cells, functional characteristics of splenocytes, and cytokine expression after whole-body irradiation at varying total doses and at low- and high-dose-rates (LDR, HDR). Young adult C57BL/6 mice (n = 75) were irradiated with either 1 cGy/min or 80 cGy/min photons from a 60Co source to cumulative doses of 0.5, 1.5, and 3.0 Gy. The animals were euthanized at 4 days post-exposure for in vitro assays. Significant dose- (but not dose-rate-) dependent decreases were observed in erythrocyte and blood leukocyte counts, hemoglobin, hematocrit, lipopolysaccharide (LPS)-induced 3H-thymidine incorporation, and interleukin-2 (IL-2) secretion by activated spleen cells when compared to sham-irradiated controls (p < 0.05). Basal proliferation of leukocytes in the blood and spleen increased significantly with increasing dose (p < 0.05). Significant dose rate effects were observed only in thrombocyte counts. Plasma levels of transforming growth factor-beta 1 (TGF-beta 1) and splenocyte secretion of tumor necrosis factor-alpha (TNF-alpha) were not affected by either the dose or dose rate of radiation. The data demonstrate that the responses of blood and spleen were largely dependent upon the total dose of radiation employed and that an 80-fold difference in the dose rate was not a significant factor in the great majority of measurements.

Animals↗

PubMedDate not supplied

Effect of pyridoxine and pyridoxal on the in vitro growth of human malignant melanoma.

The in vitro effect of vitamin B-6 supplementation on the growth of a human malignant melanoma cell line (M21-HPB) was investigated. Varying concentrations of pyridoxine (PN) or pyridoxal (PL) were added to cell cultures and incubated for 12 days. Pharmacologic levels of PL (0.25-0.5 mM) resulted in significant reductions in cell proliferation. Physiologic levels (0.005 mM) did not retard growth. Cells incubated with PN showed growth stimulation. Intracellular levels of PL and pyridoxal 5'-phosphate (PLP) were increased in cells exposed to pharmacologic PL (0.05-0.5 mM) concentrations, but not PN. These data suggest that PL or PLP may be involved in regulating the growth of melanoma cells and that vitamin B-6 may have potential use as an antineoplastic agent.

Cell Division↗

PubMedDate not supplied

Evaluation of pre-irradiation on monoclonal antibody localization in colon tumor xenografts expressing a cell-associated antigen.

We have previously demonstrated that external beam irradiation can increase radiolabeled monoclonal antibody (MAb) targeting of tumors expressing carcinoembryonic antigen (CEA), a secreted glycoprotein. Increased tumor uptake was seen with both protons and gamma radiation (60Co). However, although pre-irradiation with protons resulted in greater activity within tumors than conventional radiation, normal tissues also exhibited increased uptake. This suggested that proton beam irradiation allowed more CEA to escape and bind to radiolabeled MAb in sites other than tumor. The purpose of the present study was to determine if a similar effect could be achieved, but without an increase in normal tissue activity, with a MAb directed against a cell-bound antigen. T380 and LS174T human colon tumors were implanted s.c. into athymic nude mice and irradiated with 10 Gy 60Co or proton beam. 111In-CYT-103 MAb (anti-TAG-72) was injected i.p. 2 hr later and the biodistribution of activity was determined 2 days thereafter. Tumor size at the time of external beam irradiation and biodistribution studies was similar among the groups within each tumor type. Increased targeting of radiolabeled MAb within tumors was not observed in either model after external beam irradiation compared to their respective nonirradiated controls, although some differences were observed in normal tissue uptake. These findings demonstrate that preirradiation for the purpose of enhancing MAb delivery to the tumor site is not a universal phenomenon and may be successful only with certain antibody/tumor antigen systems.

Adenocarcinoma↗

PubMedDate not supplied

Pilot study of monoclonal antibody localization in subcutaneous and intracranial lung tumor xenografts after proton irradiation.

The purpose of this study was to determine if proton irradiation can increase the localization of radiolabeled monoclonal antibodies (MAb) in subcutaneous (s.c.) or intracranial (i.c.) human lung tumors xenotransplanted in athymic rats. Rats with carcinoembryonic antigen (CEA)-expressing (NCI-H441) tumors were irradiated using 3 different proton time-dose regimens, followed by 111In-ZCE025, an anti-CEA MAb, which was injected 2 hr after the last dose of irradiation, and the animals were euthanized 3 days later for biodistribution and other assays. Proton irradiation at 10 gray (Gy) as a single dose or in 2 Gy fractions given on 5 consecutive days increased the uptake of 111In-ZCE025 into s.c. tumors by 292% and 182%, respectively, compared to nonirradiated controls. No enhancement in radiolabeled MAb delivery was seen after hemibrain irradiation in animals with i.c. tumors. Histopathological examination of both implantation sites showed a viable poorly differentiated adenocarcinoma with a decrease in blood vessel density, a decrease in mitotic activity, and an increase in areas of necrosis following irradiation as compared with adjacent nonirradiated tissue. CEA expression was generally maintained in vivo in that the marker was detectable in the tumor, plasma, and cerebrospinal fluid. Oxygen radical production by peripheral blood cells from s.c. and i.c. tumor-bearing rats exhibited strikingly different patterns of responsiveness. I.c. injected animals were 24% lighter than their s.c. injected counterparts, but no neurological signs of tumor progression were noted. The results indicate that proton irradiation can be used effectively to increase the delivery of radiolabeled MAb to s.c. implanted human lung tumor xenografts. However, in order to accomplish this in the brain, other radiation time-dose schedules and treatments may be needed.

Adenocarcinoma↗

PubMedDate not supplied

Tumor necrosis factor-alpha augments radiation effects against human colon tumor xenografts.

Recent reports indicating that tumor necrosis factor-alpha (TNF-alpha) can augment the lethal effects of radiation against certain tumor cell lines prompted us to investigate whether this premise holds true for human colon tumor xenotransplants. Nude mice implanted s.c. with LS174T adenocarcinoma cells (day 0) were randomized into 4 groups: 1) no treatment; 2) TNF-alpha at 1 x 10(4) units/i.v. injection on days 1, 4, 8, and 10; 3) radiation at 4 Gy delivered on days 2, 5, 9, and 11; and 4) TNF-alpha + radiation administered using the same time-dose schedules as for groups 2 and 3. A decrease in tumor growth was obtained with radiation, but not TNF-alpha, as a single modality. However, significanty slower tumor growth was observed with TNF-alpha + radiation when compared to radiation alone. Blood and spleen cells from animals receiving both modalities exhibited the highest oxidative burst capacity. Histopathological evaluation showed large areas of necrosis in animals treated with radiation and with combined radiation + TNF-alpha, and only small areas of necrosis in animals treated with TNF-alpha alone. Necrosis in TNF-alpha-treated animals was not significantly larger than in controls. Irradiation of LS174T cells in culture generally decreased soluble TNF-alpha receptor and carcinoembryonic antigen in cell supernatants, but TNF-alpha was not detectable, regardless of radiation. The results show that pretreatment with TNF-alpha can significantly enhance the effects of radiation against human colon tumor xenografts and that the mechanisms of action may be related to increased oxygen radical production when both agents are administered and/or to induction of apoptosis by TNF-alpha. This data provides support for further investigations using TNF-alpha as an adjunctive agent in the radiotherapy of colon and other cancers.

Adenocarcinoma↗

PubMedDate not supplied

Effect of pre-irradiation on radiopharmaceutical localization in human colon tumor xenografts using mono- and bispecific monoclonal antibodies.

In previous investigations we found that pre-irradiation of a tumor can significantly increase site-specific accumulation of radiolabeled monoclonal antibodies (MAb). The aims of the present study were to compare the effects of radiation on the localization of conventional MAb and a bifunctional delivery system and to evaluate a new time-dose schedule. T380 human colon tumors in athymic nude mice were irradiated (60Co, 10 Gy single dose) and the antibodies were injected 2 hours later. For mice given 111In-ZCE025, an anti-carcinoembryonic antigen (CEA) MAb, the biodistribution of activity was determined 7 days later. The animals receiving ECA001, a bispecific antibody binding to CEA and to a hapten on 111In-DBX, were injected with the radiolabeled hapten 5 days after cold annbody and sacrificed 2 days later. The mean percentage of injected dose (%ID/g) within tumors was significantly increased (p < 0.05) for both anti-CEA antibodies after pre-irradiation compared to their respective nonirradiated controls (%ID/g = 22.8 versus 47.8 for conventional MAb; %ID/g = 12.5 versus 25.9 for bifunctional system). Tumor-to-normal tissue ranos were also higher in the pre-irradiated groups. The data show that pre-irradiation can increase the delivery of conventional MAb within solid tumors by over 200%. In addition, the efficacy of the approach can be enhanced by manipulation of the time-dose schedule. The results with the bispecific antibody system were unexpectedly confounded by significant differences in tumor growth rate after treatment a phenomenon not seen in the groups receiving the conventional MAb.

Animals↗

PubMedDate not supplied

Enhancement of prostate cancer xenograft growth with whole-body radiation and vascular endothelial growth factor.

Prostate cancer research has been limited by the slow growth of human prostate tumors In athymic rodent models. This study sought to determine if low-dose radiation and vascular endothelial growth factor (VEGF) could enhance the development of PC-3 human prostate adenocarcinoma xenotransplanted into nude mice. Whole body radiation (2 Gy) was delivered only once, whereas VEGF (39 ng total/mouse) was injected subcutaneously over a 17-day period. The combination of the two agents, compared to nontreated controls, resulted in significantly higher tumor incidence (100% versus 50%) and more-rapid tumor progression (1288 mm3 versus 190 mm3 by day 60). Treatment-associated changes were observed in body weights and assays of blood and spleen cells. In addition, 3H-thymidine uptake by PC-3 cells cultured in the presence of VEGF and transforming growth factor-beta 1 was compared. These results show that low-dose, whole-body radiation and VEGF can be used in concert safely and effectively to facilitate growth of PC-3 prostate tumor and that the mechanisms of interaction may involve leukocyte modulation.

Animals↗