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T J Kinsella

Publications and source records attributed to T J Kinsella.

At least 109 records · Page 6Linked to original sources
PubMed1992

Low pH does not affect the dose response for 5'-amino-5'-deoxythymidine modulation of IdUrd DNA incorporation and radiosensitization in a human bladder cancer cell line.

We report that coincubation of 647V cells for one cell cycle with low concentrations (30 microM) of 5'-amino-5'-deoxythymidine increased IdUrd DNA incorporation and radiosensitivity at low extracellular pH (pHe 6.8) in a fashion similar to treatment at normal pHe. IdUrd DNA incorporation is inhibited by high (300 microM) 5'-AdThd concentrations at both normal and low pHe (7.4 and 6.8), resulting in no significant radiosensitization. These results at low pHe were not anticipated based on previously published studies of 5'-AdThd modulation of thymidine kinase (TK) activity and nucleoside cellular uptake. Our results suggest that regulation of intracellular pH (pHi) during the course of one cell cycle negates the 5'-AdThd dose-dependent modulation of TK activity demonstrated previously. Flow cytometric measurement of pHi in 647V cells showed that normal pHi (pH 7.4) was maintained in 647V cells over a 12- to 24-h exposure to low pHe (pH 6.8). Thus the concomitant use of IdUrd and high concentrations of 5'-AdThd (> 30 microM) is unlikely to result in selective in vivo radiosensitization of human tumors under conditions which are intermittently or chronically acidic. However, low concentrations of 5'-AdThd may prove to be an effective in vivo modulator of IdUrd radiosensitization of human tumors under both normal and acidic conditions.

Cell Cycle↗
PubMed1992

The experimental and clinical rationale for the use of S-phase-specific radiosensitizers to overcome tumor cell repopulation.

Clinical and laboratory evidence suggests that several common human cancers contain populations of rapidly proliferating clonogens that may have a substantial impact on local control following conventional radiotherapy. Strategies to improve locoregional control include the use of S-phase-specific radiosensitizers, such as the halogenated pyrimidine analogues (5-iododeoxyuridine, 5-bromodeoxyuridine, fluorodeoxyuridine, 5-fluorouracil) and hydroxyurea. These drugs are taken up and metabolized only by cells synthesizing DNA so that increased tumor proliferation should result in increased radiosensitization. Although the initial clinical trials with these agents were inconclusive, several recent reports have rekindled interest in these radiosensitizers. Ongoing laboratory research has provided further insight into the basic mechanisms of radiosensitization. However, many questions remain unanswered. We will review the data that suggest rapid tumor proliferation, experimental studies with the S-phase-specific drugs, and the results of clinical trials. We will also consider the possible design of future trials based on our current understanding of tumor proliferation and the mechanisms of radiosensitization of S-phase-specific agents.

Animals↗
PubMed1992

Linear-quadratic analysis of radiosensitization by halogenated pyrimidines. I. Radiosensitization of human colon cancer cells by iododeoxyuridine.

Radiosensitization by iododeoxyuridine (IdU) is a method of enhancing cell killing in the radiotherapy of human cancers, especially for tumors that proliferate faster than the surrounding normal tissues, such as might appear in brain or liver. We have investigated in vitro the relationship between the amount of thymidine replacement by IdU and the resulting radiosensitization in two human colon cancer cell lines, HCT 116 and HT 29, with differing inherent sensitivities to X rays. The results show that an increase in the initial slope of the cell survival curve was the predominant mode of radiosensitization. In this situation, the emphasis on changes in the initial slope suggest the use of a survival curve model that contains the initial slope as a defined variable, which the traditional single-hit, multitarget model does not. We present our analyses mainly in terms of alpha (initial slope) and changes in surviving fraction at 2 Gy and also as a modified form of sensitizer enhancement ratio that describes the dose-modifying factor of IdU at a single radiation dose of 2 Gy (SER 2 Gy). Iododeoxyuridine is an effective radiosensitizer in both cell lines, but IdU appears especially effective in increasing the initial slope of the more radioresistant line, the HT 29 cells.

Cell Survival↗
PubMed1992

Linear-quadratic analysis of radiosensitization by halogenated pyrimidines. II. Radiosensitization of human colon cancer cells by bromodeoxyuridine.

As a continuation of the studies in Part I (Miller, Fowler, and Kinsella, Radiat. Res. 131, 000-000, 1992), which examined the radiosensitizing effects of iododeoxyuridine (IdU), similar experiments with bromodeoxyuridine (BrdU) were conducted concurrently to characterize its effects on the shape of the radiation survival curves of cells of two human colon cancer cell lines, HT 29 and HCT 116. The efficiency of radiosensitization by BrdU, expressed as a function of percentage thymidine replacement, was lower when compared to IdU in both cell lines. However, the major radiosensitizing effect of BrdU was manifest as an increase in the initial slope (alpha), just as observed for IdU. However, with BrdU, in contrast to IdU, an increase in curvature (repairable damage) was also evident. Cells of the more radiosensitive line, HCT 116, showed less sensitization by either BrdU or IdU than cells of the more radioresistant line, HT 29. These results were consistent with the proposed mechanism of radiosensitization being an increase in the single-hit character of low-LET radiation. It follows that the radiosensitizing effects of both analogs were largest in the low-dose region of the survival curve.

Bromodeoxyuridine↗
PubMed1992

Radiosensitization and cell kinetics: clinical implications for S-phase-specific radiosensitizers.

Rapid repopulation of tumor cells during conventional radiation therapy has been recently recognized as a factor that might significantly impair tumor response in several different tumor sites. One clinical strategy to overcome rapid tumor proliferation is to use S-phase-specific radiosensitizers such as hydroxyurea and the halopyrimidines 5-iododeoxyuridine (IUDR), 5-bromo-2'-deoxyuridine (BUDR), 5-fluoro-2'-deoxy-beta-uridine (FUDR), and 5-fluorouracil (5-FU). Indeed, several recent clinical trials have shown the positive antiproliferative effects of these radiosensitizers in various human tumors. In spite of this resurgence of clinical interest, the basic mechanism(s) of radiosensitization is not clearly understood. Although the halopyrimidines have similar biochemical pathways involving two key regulatory enzymes, thymidine kinase and thymidylate synthase, it appears that DNA-incorporation is important for radiosensitization by BUDR and IUDR but not for FUDR or 5-FU. Recent laboratory data suggest that biochemical modulation of the key regulatory enzymes can result in selective tumor radiosensitization with halopyrimidines. Hydroxyurea, like 5-FU, sensitizes cells when present prior to and following irradiation; this interaction may be related to cell synchronization as well as altered DNA damage repair. Exploiting differences in cell proliferation and cellular metabolism of these S-phase-specific radiosensitizers in tumors and normal tissues will be a major focus of clinical research in human tumor radiosensitization over the next few years.

Cell Cycle↗
PubMed1991

Prognostic value of histopathology in Ewing's sarcoma. Long-term follow-up of distal extremity primary tumors.

The pathologic material from 56 patients diagnosed initially as Ewing's sarcoma of the distal extremity and treated on National Cancer Institute protocols between 1968 and 1984 was reviewed and correlated with clinical outcome. Histologically, the tumors were categorized, based on recent pathologic criteria, into three diagnostic groups: (1) typical Ewing's sarcoma, (2) atypical Ewing's sarcoma, and (3) other (predominantly peripheral neuroepithelioma [PN]). Thirty-two patients (57%) had typical Ewing's, 13 (23%) were atypical, and 11 (20%) were in the "other" diagnostic category (seven [13%] PN, two primitive rhabdomyosarcoma, one primitive sarcoma of bone, and one synovial cell sarcoma). No cases of metastatic neuroblastoma, osteosarcoma, or lymphoma were found. Forty-five patients had localized disease at diagnosis; 11 had metastases. Patients with typical Ewing's sarcoma were less likely to have metastatic disease at the time of diagnosis. Only two of 32 patients with typical Ewing's sarcoma had metastases compared with nine of 24 patients in the two other groups. The pattern of relapse was also different in these other groups compared with typical Ewing's patients; five patients developed lymph node metastases and two patients developed brain metastases. Although the presence of metastatic disease at diagnosis was a strong negative prognostic factor, our histologic grouping was independently prognostic of clinical outcome in patients with localized disease. Patients with typical osseous Ewing's sarcoma had an improved overall survival (P2 = 0.03) and patients with other tumors (neither typical nor atypical Ewing's sarcoma) had a poorer disease-free survival (P2 = 0.02). Since no generally accepted histopathologic prognostic criteria exist for Ewing's sarcoma, the potential value of our proposed classification should be evaluated in a larger retrospective and a prospective study.

Adolescent↗
PubMed1991

Threshold dose for peripheral neuropathy following intraoperative radiotherapy (IORT) in a large animal model.

Radiation injury to peripheral nerve is a dose-limiting toxicity in the clinical application of intraoperative radiotherapy, particularly for pelvic and retroperitoneal tumors. Intraoperative radiotherapy-related peripheral neuropathy in humans receiving doses of 20-25 Gy is manifested as a mixed motor-sensory deficit beginning 6-9 months following treatment. In a previous experimental study of intraoperative radiotherapy-related neuropathy of the lumbro-sacral plexus, an approximate inverse linear relationship was reported between the intraoperative dose (20-75 Gy range) and the time to onset of hind limb paresis (1-12 mos following intraoperative radiotherapy). The principal histological lesion in irradiated nerve was loss of large nerve fibers and perineural fibrosis without significant vascular injury. Similar histological changes in irradiated nerves were found in humans. To assess peripheral nerve injury to lower doses of intraoperative radiotherapy in this same large animal model, groups of four adult American Foxhounds (wt 20-25 kg) received doses of 10, 15, or 20 Gy to the right lumbro-sacral plexus and sciatic nerve using 9 MeV electrons. The left lumbro-sacral plexus and sciatic nerve were excluded from the intraoperative field to allow each animal to serve as its own control. Following treatment, a complete neurological exam, electromyogram, and nerve conduction studies were performed monthly for 1 year. Monthly neurological exams were performed in years 2 and 3 whereas electromyogram and nerve conduction studies were performed every 3 months during this follow-up period. With follow-up of greater than or equal to 42 months, no dog receiving 10 or 15 Gy IORT shows any clinical or laboratory evidence of peripheral nerve injury. However, all four dogs receiving 20 Gy developed right hind limb paresis at 8, 9, 9, and 12 mos following intraoperative radiotherapy. These experimental data suggest that intraoperative doses of less than 20 Gy may not result in clinically significant peripheral nerve injury with follow-up of 3.5 years. Longer (5 yrs) follow-up with planned sacrifice of the remaining dogs is scheduled to assess any late peripheral nerve damage.

Animals↗
PubMed1991

Long-term follow-up of Ewing's sarcoma of bone treated with combined modality therapy.

Between 1968 and 1980, 107 consecutive patients with Ewing's sarcoma of bone were entered on three sequential combined modality treatment protocols (S2, S3, S4) at the National Cancer Institute (NCI). Protocol treatment involved 4 cycles of two drug [cyclophosphamide (CTX) and vincristine (VCR)] or three drug [CTX and VCR with either actinomycin-D (ACT-D) or doxorubicin (ADR)] regimens and local irradiation (50 Gy) to the involved bone. Eighty patients presented with localized disease and 27 patients had metastatic disease at presentation, including 11 patients with multiple metastatic sites. With a median potential follow-up of greater than 15 yrs (range 8-20 yrs), 28 pts (27%) remain alive. Disease-free (DFS) and overall survival (OS) decreased most rapidly during the initial 5 yrs of follow-up with 5-yr DFS of 29% and 5-yr OS of 39%. Only two patients with metastases at presentation are long term (greater than 5 yr) survivors. For localized disease patients, the 2, 5, 10, and 15 yr DFS and OS are 52%, 37%, 35%, and 33% DFS and 68%, 51%, 39%, and 34% OS, respectively. Eleven patients relapsed locally as the first site of failure. Using the Cox proportional hazards model, four significant variables for both DFS and OS were recognized, including metastatic disease at presentation, age greater than 25 yrs, high LDH in localized disease patients, and central primary tumor in localized disease patients in decreasing order of significance. We conclude that a majority of these patients with Ewing's sarcoma of bone relapsed within 5 yrs of presentation although late relapse (5-15 yrs) did occur. Local failure occurred in 20% of patients using these combined modality treatments but had no impact on overall survival.

Adolescent↗
PubMed1991

Keynote address: integration of cytostatic agents and radiation therapy: a different approach to "proliferating" human tumors.

Failure to achieve local and regional tumor control with radiation therapy remains a significant problem for a number of anatomic sites and can have a negative impact upon survival. There is emerging clinical and laboratory evidence that proliferation of tumor clonogens during the course of radiation treatment significantly impairs local control. Recent in situ studies suggest that as many as half of all human carcinomas have the potential to double their cell number in 5 or fewer days. Thus, cells that survive the initial treatments might rapidly repopulate a tumor, resulting in local failure. One potential clinical approach to reduce the impact of tumor cell repopulation during treatment would be to administer biological or chemical modifiers to slow or inhibit tumor proliferation. Examples of these cytostatic modifiers which are available for clinical testing now, or in the near future, include hormones, anti-hormones, growth factors, growth factor antagonists and other biologicals (e.g., interferons). Clinical alteration of the proliferative status of tumors could influence tumor control by reducing the impact of tumor cell proliferation during therapy, by modifying tumor cell radiosensitivity, or by favourably altering both. To appreciate the magnitude and the cumulative effect of these factors, newer technologies and experimental model systems need to be exploited in investigating correlations between proliferation and tumor control and between proliferative status and radiosensitivity. The design of future clinical trials using cytostatic agents and radiotherapy will rely heavily upon such basic information.

Antineoplastic Agents↗
PubMed1991

Early changes in tumor metabolism after treatment: the effects of stereotactic radiotherapy.

Four patients with intracranial neoplasms, two with malignant gliomas and two with brain metastases, were treated with stereotactic radiotherapy. Patients received between 15 and 27.5 Gray of photon irradiation to the central tumor target point; the 80% isodose line covered the periphery of the tumor as determined by contrast enhanced computed tomography. Patients underwent a sequence of three Positron Emission Tomographic scans using [18F]-fluorodeoxyglucose (PET-FDG)--a baseline scan the day before treatment, and follow-up scans 1 and 7 days after treatment. Ratios between the maximal tumor regional cerebral metabolic rate for glucose (rCMRGlu) (T*) and the contralateral remote white matter rCMRGlu (RW), that is, the glucose uptake ratio (T*/RW), were calculated. The percent change in ratios relative to each patient's baseline scan were calculated. Ratios increased 25% to 42% 1 day post-radiotherapy, then decreased to between 10% above and 12% below the baseline value 7 days post-radiotherapy. The T*/RW increased acutely after stereotactic radiotherapy in a fashion similar to that previously described following chemotherapy with a complex multi-drug regimen. A common metabolic pathway may underlie the increase in T*/RW after these different treatments.

Brain Neoplasms↗
PubMed1991

A three-dimensional volume visualization package applied to stereotactic radiosurgery treatment planning.

A comprehensive software package has been developed for visualization and analysis of 3-dimensional data sets. The system offers a variety of 2- and 3-dimensional display facilities including highly realistic volume rendered images generated directly from the data set. The package has been specifically modified and successfully used for stereotactic radiosurgery treatment planning. The stereotactic coordinate transformation is determined by finding the localization frame automatically in the CT volume. Treatment arcs are specified interactively and displayed as paths on 3-dimensional anatomical surfaces. The resulting dose distribution is displayed using traditional 2-dimensional displays or as an isodose surface composited with underlying anatomy and the target volume. Dose volume histogram analysis is an integral part of the system. This paper gives an overview of volume rendering methods and describes the application of these tools to stereotactic radiosurgery treatment planning.

Brain Diseases↗
PubMed1991

Combined modality therapy.

Encouraging results continue to emerge with the use of chemoradiotherapy. This review of the current literature demonstrates some of the advances that have been achieved in a variety of common malignancies with strategies based on well-defined rationales. Preliminary randomized trials now reveal a survival advantage for chemoradiotherapy in patients with inoperable non-small cell lung cancer and patients with rectal cancer at high risk for recurrence following resection. Other studies report that concurrent chemoradiotherapy may improve local control in patients with limited-stage, small cell lung cancer or esophageal malignancies. The additional toxicity of these approaches is discussed.

Combined Modality Therapy↗
PubMed1990

Modulation of IdUrd-DNA incorporation and radiosensitization in human bladder carcinoma cells.

5' Amino-5'-deoxythymidine (5'-AdThd) has been demonstrated previously to antagonize dTTP-mediated feedback inhibition of purified thymidine kinase from 647V, a human bladder cancer cell line. Low concentrations of 5'-AdThd (3-30 microM) have also been shown to stimulate cellular uptake of iododeoxyuridine (IdUrd) in 647V cells at clinically relevant IdUrd concentrations (2 microM). We report that the combination of 30 microM 5'-AdThd plus 2 microM IdUrd results in a significant increase of IdUrd replacement of thymidine (dThd) (18%) in the DNA of 647V cells over that obtained by exposure to 2 microM IdUrd alone (7.9%). However, increasing the 5'-AdThd concentration to 300 microM inhibited the incorporation of IdUrd into DNA (3%). IdUrd-induced radiosensitization of 647V cells, as measured by clonogenic survival, was enhanced by coincubation with 30 microM 5'-AdThd, while 300 microM 5'-AdThd reduced the IdUrd radiosensitization. Additionally, radiation-induced single strand break generation when IdUrd was incorporated into 647V DNA, as measured by rapid alkaline elution, was also enhanced by coincubation with 30 microM 5'-AdThd, while 300 microM 5'-AdThd resulted in a decrease in the number of single strand breaks produced. In T24, another bladder cancer cell line, and SV-HUC-TT1, a tumorigenic cell line derived from SV-HUC, 3-10 microM 5'-AdThd was also able to enhance IdUrd replacement of dThd in DNA. However, no stimulation of dThd replacement by 5'-AdThd occurred in SV-HUC, a prototypic "normal" bladder urothelial cell line. Since 5'-AdThd is not a substrate for mammalian thymidine kinase and has little or no cytotoxicity in vitro and in vivo, it may be a selective modulator of IdUrd radiosensitization of human bladder carcinoma and should be tested in vivo.

Carbon Radioisotopes↗
PubMed1990

Monte Carlo and convolution dosimetry for stereotactic radiosurgery.

The dosimetry of small photon beams used for stereotactic radiosurgery was investigated using Monte Carlo simulation, convolution calculations, and measurements. A Monte Carlo code was used to simulate radiation transport through a linear accelerator to produce and score energy spectrum and angular distribution of 6 MV bremsstrahlung photons exiting from the accelerator treatment head. These photons were then transported through a stereotactic collimator system and into a water phantom placed at isocenter. The energy spectrum was also used as input for the convolution method of photon dose calculation. Monte Carlo and convolution results were compared with the measured data obtained using an ionization chamber, a diode, and film.

Brain Neoplasms↗
PubMed1990

Enhancement of radiation damage in cellular DNA following unifilar substitution with iododeoxyuridine.

The exact mechanism of x-ray radiosensitization with iododeoxyuridine (IdUrd) is not known. Using log phase V79 cells, we compared radiosensitization following unifilar (9 hr exposure) and bifilar (17 hr exposure) substitution with 10(-5) M IdUrd. The % thymidine replacement was 8% and 16%, respectively. Significant radiosensitization was found with unifilar (Do = 1.35 Gy, n = 5.8) and bifilar substitution (Do = 1.2 Gy, n = 4.0) compared to controls (Do = 1.7 Gy, n = 8.5). Using filter elution techniques, the enhancement ratios (ER) for double strand breaks (SB) were 1.5 and 2.0 for unifilar and bifilar substitution, respectively, whereas the enhancement ratio for single strand breaks were both greater than or equal to 2.1. Comparing the enhancement ratios with unifilar substitution for single strand breaks in substituted (2.4) and unsubstituted complement strands (1.9) as well as in unsubstituted duplex DNA (1.4) in cells containing IdUrd substituted DNA, there was increased damage in unsubstituted strands compared to irradiated controls. These data suggest that in vitro radiosensitization following unifilar substitution with IdUrd results, in part, from damage to unsubstituted complementary strand and adjacent doubly unsubstituted DNA. The radiolysis of halogenated DNA produces mobile reactive intermediates which may cause intermolecular DNA damage such as single strand breaks in unsubstituted DNA and resultant double strand breaks and this damage is probably responsible for increased lethality after x-irradiation.

Animals↗
PubMed1990

90Y.B72.3 against pancreatic cancer: dosimetric and biological analysis.

Nude mice xenografted with a human pancreatic carcinoma cell line were injected with yttrium-90 (90Y) conjugated to diethylene triaminepenta acetic acid (DTPA) alone, and DTPA covalently linked to a monoclonal antibody, B72.3. The animals were sacrificed in temporal sequence to evaluate isotope distribution. Dosimetry was carried out using the principles outlined in MIRD and ICRU Report 32. Results are expressed as percent uptake per unit mass in organs and tumor and as relative absorbed dose normalized to 90Y uptake in liver at 7 hr. When conjugated to B72.3, an 8-fold increase in isotope localization in the tumor was noted by 24 hr. When the relative absorbed dose is calculated for 90Y and 90Y.B72.3, a 26-fold increase in tumor dose is noted for the 90Y conjugate. Normal tissues show no to modest (less than 5x) enhanced dose with 90Y.B72.3. B72.3, therefore, deserves further investigation as a potential monoclonal antibody for targeting therapeutic radioisotopes and possibly diagnostic radioisotopes to pancreatic cancer. Radiobiological aspects of the low dose rates from radioimmunotherapy are discussed.

Animals↗