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Biomedical subjects

T J Kinsella

Publications and source records attributed to T J Kinsella.

204 records · Page 12Linked to original sources
PubMedDate not supplied

Experimental and clinical studies of intraoperative radiation therapy.

Intraoperative radiation therapy (IORT) is an innovative treatment modality that has recently been given considerable attention as an approach toward controlling various locally advanced cancers. IORT involves surgical extirpation or debulking of the malignant lesion and the delivery of a large single dose of radiation to the tumor bed or to residual disease. This strategy allows for a theoretical enhancement of the therapeutic effect of radiation for three reasons: (1) the biologic effectiveness of a single large radiation dose is higher than for the same dose given in a fractionated regimen; (2) the dose of radiation is precisely given to the area at greatest risk of tumor recurrence (or persistence); and (3) irradiation of dose-limiting normal tissues may be avoided by operative mobilization of the tissues from the treatment volume by customized lead shielding of anatomically fixed structures or by judicious choice of electron beam energies or use of a bolus to limit dose to deep structures. Electrons are generally used for IORT because of sharp dose falloff. This avoids potential toxic effects to normal structures that may lie deep to the treatment volume. Conventional external beam photon radiation therapy (EBRT) allows less accurate tumor volume delineation (even with sophisticated treatment planning technique) and dose limitations necessitated by normal tissues incidentally in the treatment volume. A considerable amount of experimental and clinical data are available on the acute and late effects of IORT on normal tissues. Dose tolerances of many organs have been described in large animal models, and clinical toxicities are evident in several trials. Clinical IORT treatments are provided in more than 250 U.S. and foreign centers at the present time. Given the current interest in IORT, this monograph will review IORT methods and experimental and clinical results with emphasis on its present and future role for locally advanced cancers.

Animals↗
PubMedDate not supplied

Cell cycle regulation of the G0/G1 transition in 5-fluorouracil-sensitive and -resistant human colon cancer cell lines.

PURPOSE: Resistance to 5-fluorouracil (5-FU) has been associated with thymidylate synthase (TS) gene amplification and increased TS protein levels. Increased TS protein expression has also been found to be a significant independent prognostic factor for disease-free survival and overall survival in patients treated with adjuvant 5-FU-based chemotherapy. In these studies and in our prior preclinical studies, TS has been considered a marker of proliferative capacity. The purpose of the current study was to further evaluate the association between TS levels and cell cycle regulation, by investigating cell cycle kinetics in a 5-FU-resistant cell line with constitutive overexpression of TS. The influence of increased TS levels on cell cycle progression may provide insight into methods to overcome 5-FU resistance. MATERIALS: 5-FU-sensitive NCI H630(WT) and 5-FU-resistant NCI H630(R1) (with 15- to 20-fold higher TS protein levels) were utilized in this investigation to determine the influence of constitutive overexpression of TS on cell cycle kinetics. RESULTS: There was no apparent influence of increased TS levels on cell cycle distribution during asynchronous growth, and both cell lines reach plateau growth phase in 120 hours, arresting in G0/G1 as determined by flow cytometry. In the H630(WT) cells, this G0/ G1 arrest was associated with a 14- to 17-fold reduction in TS activity and protein levels (using the TS-106 monoclonal antibody), whereas in the H630(R1) cells, only a two- to fivefold reduction was noted. Flow cytometry analysis utilizing Ki-67 indicated that there was no evidence of a G0 population in the confluent H630(R1), whereas 26% +/- 7% of confluent H630(WT) cells were Ki-67 negative (G0) and the remainder had low Ki-67 signal intensity. Analysis of pRb phosphorylation and p16 and p21 expression suggested that the arrest point for both cell lines was before the point at which Rb phosphorylation takes place, yet the confluent H630(R1) cells had threefold higher p21 than confluent H630(WT) cells. DISCUSSION: These data suggest that the 5-FU-resistant H630(R1) cell lines arrest at a later point in G0/G1 and have a potentially greater capacity for proliferation.

Antimetabolites, Antineoplastic↗
PubMedDate not supplied

The interaction of hydroxyurea and ionizing radiation in human cervical carcinoma cells.

PURPOSE: The results from prior in vitro and in vivo studies and recent phase 3 clinical trials suggest a significant potential role for hydroxyurea (HU) as a clinical radiosensitizer for cervix cancer. However, a detailed study of possible cellular mechanisms of radiosensitization in human cervix cancer cells as a consequence of dose and timing of HU and ionizing radiation (IR) has not been performed. This in vitro study analyses the interactions of HU and IR in a human cervical carcinoma cell line, Caski. MATERIALS AND METHODS: Exponentially growing Caski cells were continuously exposed to clinically achievable but minimally cytotoxic concentrations of HU (0.3-3.0 mM) for various time intervals (6, 12, 18, 24, and 30 hours) up to one population doubling time either prior to or immediately following IR (2-8 Gy). The radiation survival data were analyzed using our modification of the linear-quadratic model to test for an interaction (greater than additive). The effects of HU alone, IR alone, and the combination on cell cycle progression and on apoptotic cell death in exponentially growing Caski cells were measured. RESULTS: We report a significant HU-IR interaction (radiosensitization) based on the sequence of HU exposure (post- > pre-IR) and with increasing concentrations of HU (0.3-3.0 mM), but no effect on radiosensitization with the duration of exposure to HU for up to one cell population doubling (6-30 hours). HU concentration has a significant effect on both alpha and beta linear-quadratic values in the post-IR sequences. Exposures of exponentially growing Caski cells to 1 mM and 3 mM HU alone result in a complete block in early S phase throughout the 30-hour exposure, while 0.3 mM HU causes a transient early S-phase block over the initial 12 to 18 hours of exposure. HU alone has no effect on cell cycle progression in G1 or G2/M populations but results in a large apoptotic population (31% following 1 mM HU x 30 hours), which appears to be the principal mechanism of drug cytotoxicity in these cells. IR alone (4 or 6 Gy) results in a significant G2 delay for 6 to 18 hours following IR but no G1 delay and a small apoptotic population at 30 hours post-IR (5.4% vs 2.1% in non-IR controls). The use of HU (0.3 or 1.0 mM) following IR (4 or 6 Gy) results in a significantly larger G2 delay compared with IR alone, but with only an additive effect on the apoptotic population. CONCLUSIONS: These in vitro data demonstrate that radiosensitization of Caski cells is more significant with post-IR exposures to clinically achievable concentrations of HU. This HU-IR interaction is associated with an increased G2 delay, suggesting a reduction in IR damage repair. However, this interaction appears to be independent of the cytotoxicity (principally by apoptosis) from HU alone.

Apoptosis↗
PubMedDate not supplied

Iododeoxyuridine radiosensitization of human glioblastoma cells exposed to acute and chronic gamma irradiation: mechanistic implications and clinical relevance.

PURPOSE: Iododeoxyuridine (IdUrd) is a recognized sensitizer of sparsely and some densely ionizing radiations. The mechanism of sensitization remains uncertain. Sensitization is likely to involve increased production of DNA damage and/or inhibition of DNA damage repair. To test these possibilities, we have characterized acute and chronic radiosensitization, and the sublethal damage repair capacity of two human glioblastoma cell lines, with or without clinically relevant concentrations of IdUrd. MATERIALS AND METHODS: Exponentially growing human glioblastoma cell lines, G18 and U251, were irradiated with acute (1.4 Gy/min) and chronic (20, 40, and 80 cGy/hr) cobalt 60 exposures in the presence and absence of 0 to 10 microM IdUrd. Clonogenic survival was determined. Sensitizer enhancement ratios and global survival curve comparisons were determined with and without IdUrd. Repair half-times for chronic exposures with and without IdUrd were calculated. Split-dose recovery following acute fractions of 5 Gy separated by 0, 0.5, 1, 2, and 5 hours was evaluated. RESULTS: Following acute exposure, a sensitizer enhancement ratio at 10% survival of 1.85 and 1.75 was observed at concentrations of 10 microM IdUrd for the G18 and U251 cell lines, respectively. A global comparison of the survival curves similarly revealed significant sensitization at 10 microM IdUrd. Sensitizer enhancement ratios and global comparisons of the chronic exposures showed significant sensitization in the presence of 2 microM IdUrd for both lines. No significant interaction between dose rate and IdUrd effect could be shown using a global comparison. Repair half-times for chronic exposures were similar in the presence or absence of IdUrd. Both cell lines demonstrate capacity for sublethal damage repair in the presence of 2 microM IdUrd in split-dose experiments. CONCLUSION: The results of the chronic clonogenic and split-dose studies suggest that increased DNA damage production contributes to the mechanism of IdUrd radio-sensitization, perhaps more so than repair inhibition. A capacity for sublethal damage repair is not necessarily a prerequisite for sensitization. IdUrd remains an attractive sensitizer of ionizing irradiation delivered at high or low dose rates, particularly for actively growing tumors located in quiescent normal tissues.

DNA Damage↗
PubMedDate not supplied

An approach to the radiosensitization of human tumors.

The use of biochemical modifiers of nucleotidc metabolism as clinical radiosensitizers holds renewed interest in the oncology community in light of the recently reported positive clinical trials cited in this article. In general, this approach to radiosensitization attempts to limit the effect of tumor repopulation and to reduce the efficiency of radiation damage repair in tumors during treatment. Since these drug-radiation interactions lack tumor specificity, further improvements in the therapeutic gain can only result by identifying exploitable differecnces in the biologic properties of tumors and dose-limiting normal tissues. The rapid evolution of our understanding of differences in cell cycle regulation in rumors and normal tissues is clearly one area that will likely provide new strategies for these combined modality approaches.

Animals↗