bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potentiation of antineoplastic drugs in vitro and in vivo by DNA intercalating bioreductive agents
Authors: Papadopoulou Maria V. , Miller Anna , Seskey Troy , Epperly Michael W. , Bloomer William D. 
Published: February 2007

AbstractThree recently synthesized 2‐nitroimidazole‐linked acridine DNA intercalators (NLA‐1, NLA‐2, and NLA‐4) have been studied as potentiators of the cytotoxic effect of melphalan (L‐PAM), 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU), cis‐diamminedichloroplatinum (II) (cis‐DDP), and doxorubicin in V79 cells. In vivo studies have also been performed with all three sensitizers and L‐PAM, while NLA‐1 alone was examined for potentiation of cis‐DDP, using C3H/HEJ mice, bearing a murine ovarian tumor. Significant chemosensitization was observed in vitro with L‐PAM, CCNU, and cis‐DDP after hypoxic preincubation treatment of the cells (37°C) at negligible concentrations of each sensitizer, while inhibition was observed with doxorubicin. Long hypoxic preexposure times at relatively low sensitizer doses were more effective than short hypoxic preexposure times at high sensitizer doses for potentiation. Glutathione depletion studies in vitro with diethyl maleate (DEM) showed that only less than half of the enhanced toxicity observed with NLA‐1 or NLA‐4 and L‐PAM is due to glutathione depletion by the sensitizer. The LD50/35 value in C3H/HEJ mice for NLA‐1, NLA‐2, and NLA‐4 was 45, 25, and 63 mg/kg, respectively. Significant antitumor effect was observed in vivo when 25 mg/kg of NLA‐1 was administered i.p. to tumor‐bearing mice 2 hr before L‐PAM administration (2.5 mg/ kg, i.p.). With this combination pattern of sensitizer:antineoplastic drug, 50% cures were observed in mice followed for >150 days; no long‐term survivors were observed with L‐PAM therapy alone. © 1993 Wiley‐Liss, Inc.
Low dose‐rate irradiation of human glioma cells and thermoradiosensitization by mild hyperthermia
Authors: Heller Dennis P. , Raaphorst G. Peter 
Published: February 2007

AbstractHuman brain tumors are clinically very resistant to radiation therapy. Recent clinical trials of combined simultaneous brachytherapy and mild hyperthermia have shown great promise. In this study two relatively radioresistant human glioma cell lines have been irradiated in plateau growth phase under low dose‐rate (LDR) conditions (<1 cGy/min) with and without concurrent mild (39–41°C) hyperthermia. The large degree of LDR sparing observed at 0.88 cGy/min (LDR1) was almost completely inhibited by concurrent heating at 41°C, resulting in a thermal enhancement ratio (TER) of 1.6 and 1.8 at the 1% survival level for U‐87MG and U‐373MG, respectively. At 0.41 cGy/min (LDR2) concurrent heating at 41°C resulted in greater thermoradiosensitization for U‐87MG (TER 2.1) and less thermoradiosensitization for U‐373MG (TER 1.5). For U‐87MG, thermoradiosensitization with LDR2 at 39 and 40°C was similar and suboptimal compared with concurrent 41°C hyperthermia. For U‐373MG, thermoradiosensitization was nearly absent at both 39 and 40°C. The direct cytotoxicity of 39, 40, and 41°C heating was similar in both cell lines. Survival after 48 hr of heating at 41°C was not less than 30% for either cell line. Hyperthermia delivered prior to LDR irradiation has shown varying degrees of sensitization both in vitro and in vivo. In this study, preheating with 8 hr at 41°C did not sensitize 9 Gy LDR2 at 37°C; however, 1 hr at 43°C did result in some thermoradiosensitization with a survival reduction factor (SRF) of 1.4. With 9 Gy LDR2 delivered at 41°C, preheating did result in additional thermoradiosensitization (SRF of 1.6, 3.5, respectively). The significant degree of thermoradiosensitization seen with concurrent LDR irradiation and 41°C hyperthermia with or without preheating supports the promising results seen in recent clinical trials. © 1993 Wiley‐Liss, Inc.
Radiobiology and radiation treatment of malignant melanoma: A review
Authors: Peschel Richard E. 
Published: February 2007

AbstractThe incidence of malignant melanoma (MM) has one of the fastest growth rates in the world and external beam radiation therapy (RT) is an important component in the total therapeutic management of MM. The radiobiology of MM provides a fascinating example of the complexities of radiation tumor biology. Both the multitarget model and the linear quadratic model predict that high dose per fraction (HDPF: 400 cGy or more) RT may be more efficacious than low dose per fraction (LDPF: 180–300 cGy) RT for some MM. However, other radiobiological factors such as repair of potentially lethal damage, reoxygenation, and repopulation appear to support the use of LDPF RT. Therefore, the MM radiobiological data predict a diverse response to a wide spectrum of HDPF and LDPF time‐dose prescriptions. The clinical data for MM are consistent with these radiobiological predictions. MM exhibits a high response rate to both HDPF and LDPF time‐dose prescriptions. RT is an effective therapy for MM in many clinical settings: 1) RT is the single most effective local therapy for metastatic disease with complete response rates of 23–72% and long‐term local tumor control rates of 48–82%; 2) heavy ion RT is the primary treatment for many ocular MM with 5‐year eye retention rates of 89% and 5‐year local tumor control rates of 96%; 3) RT is the treatment of choice for mucosal non‐cutaneous, non‐ocular MM with results that are equal or superior to radical surgery; and 4) recent reports suggest an important role for adjuvant RT in postoperative patients who are at high risk for local‐regional recurrence. The current roles for RT in MM should be reevaluated since it is likely that RT is being underutilized in the overall clinical management of MM. © 1994 Wiley‐Liss, Inc.
Tolerance of rhesus monkey liver to ionizing radiation
Authors: Stephens L. Clifton , Peters Lester J. , Ang K. Kian 
Published: February 2007

AbstractThis study was undertaken to determine if nonhuman primates are suitable models for the veno‐occlusive disease (VOD) that characterizes radiation hepatopathy in man. Adult rhesus monkeys had near total liver irradiation to 36 Gy in 8 fractions (Group 1, n = 5) or to 50 Gy in 20 fractions (Group II, n = 5). All had normal liver function and no lesions in liver biopsies 9 months after irradiation. A monkey from each group was given either doxorubicin, cyclophosphamide, cisplatin, or methotrexate over a 15‐week period. The one given 36 Gy in 8 fractions and doxorubicin died of congestive heart failure 1 month after the last course. The remainder of Group 1 animals had normal liver function and morphology 2 to 3 years after therapy. Group II animals given methotrexate or cisplatin had the liver retreated with 30 Gy in 30 fractions at 2 years after receiving 50 Gy in 20 fractions. Within 1 month, the animal given methotrexate developed massive hepatic necrosis. The other given a cumulative liver dose of 80 Gy remained clinically normal. This animal and the others in Group II underwent left hepatic lobectomy 2 years after the first radiation course. All had normal liver function and no VOD when they were sacrificed 1 year later. A monkey given methotrexate followed by liver irradiation (50 Gy in 20 fractions) developed hepatic necrosis 10 months later. Another given cyclophosphamide and 50 Gy in 20 fractions was normal for 2 years after treatment.In summary, none of the monkeys developed classical VOD, and they apparently were resistant to induction of significant hepatic injury by radiation alone. Occult radiation injury was not exacerbated by either chemotherapy or partial hepatectomy.Hepatic necrosis in this model was induced by methotrexate administration followed by liver irradiation. The reason for the difference in radiosensitivity of the monkey liver and human liver is unknown. © 1994 Wiley‐Liss, Inc.
Porfiromycin as an adjunct to radiation therapy in squamous cell carcinoma of the head and neck: Results of a phase I clinical trial
Authors: Haffty Bruce G. , Son Yung H. , Moini Marjaneh , Papac Rose , Fischer Diana , Rockwell Sara , Sartorelli Alan C. , Fischer James J. 
Published: February 2007

AbstractPurpose: A phase I toxicity trial aimed at defining an appropriate dose of the bioreductive alkylating agent porfiromycin to be used in conjunction with radiation therapy in patients with squamous cell carcinoma of the head and neck. Methods and Materials: A total of 21 patients were entered into this phase I clinical trial. All patients had locally advanced squamous cell carcinoma of the head and neck and were treated with radiation therapy with or without surgical intervention. Porfiromycin was administered on days 5 and 47 of the course of radiation therapy. The initial dose of the drug was 50 mg/M2, but due to hematological toxicity the dose was lowered to 40 mg/M2. The final 12 of the 21 patients in this phase I clinical trial was treated at the dose of 40 mg/M2. Radiation therapy was directed at the primary site and regional lymph nodes as clinically indicated with conventional fractionations of 200 cGy/day to total doses in excess of 6,000 cGy. Results: Five patients were treated at the initial dose of 50 mg/M2, but due to excessive hematologic toxicity the dose was reduced to 45 mg/M2 for 4 patients and lowered again to 40 mg/M2 for the final 12 patients of the study. As expected, the major toxicity was hematological with thrombocytopenias and neutropenias. There were no clinically evident bleeding episodes secondary to thrombocytopenia and no neutropenic deaths during the course of the study. Of the 21 patients treated in the series, 10 remain alive no evidence of disease (NED) with a median follow‐up of 18.5 months. Four of the alive NED patients have been followed for over 2 years. Conclusions: The bioreductive alkylating agent porfiromycin may be safely administered at a dose of 40 mg/M2 to patients undergoing radiation therapy for squamous cell carcinoma of the head and neck. Based on the results of this phase I trial, we have now mounted a phase III clinical trial in patients with all stages of squamous cell carcinoma of the head and neck, comparing radiation therapy with porfiromycin to radiation therapy with mitomycin C. There is no radiation therapy without drug in this phase III clinical report. © 1994 Wiley‐Liss, Inc.
Role of transforming growth factor‐β and hepatocyte growth factor in late normal tissue effects of radiation
Authors: Anscher Mitchell S. , Jirtle Randy L. 
Published: February 2007

AbstractConventional radiation therapy practice (i.e., dose, field size, beam arrangement, fraction size, etc.) has been largely derived empirically from decades of clinical observation. Much emphasis has been placed upon maximizing the dose to the tumor while minimizing the risk of complications. In practice, however, it is often the normal tissues that limit the total dose of radiation that can be delivered to the tumor since excessive doses of radiation frequently result in severe fibrotic reactions developing in the exposed normal tissues. It is now becoming apparent that growth factors, in particular Transforming Growth Factor‐β (TGF‐β) and Hepatocyte Growth Factor (HGF), are important mediators in the repair of normal tissue injury under a variety of circumstances, including following radiotherapy or chemotherapy. Herein, we have discussed the evidence implicating HGF and TGF‐β in normal tissue repair and fibrosis formation, and describe their potential usefulness as predictors of late normal tissue damage. © 1994 Wiley‐Liss, Inc.
Tumor growth retardation and pathophysiological effects of adenosine 5′‐triphosphate therapy measured by thallium washout, 31P nuclear magnetic resonance, laser doppler flowmetry, and intradermal angiogenesis
Authors: Okunieff Paul , Froio John , Soni Rajesh , Kahn Julia , Gerweck Leo , Zlotecki Robert , Abraham Edward H. 
Published: February 2007

AbstractTransplants of a spontaneous murine fibrosarcoma (FSaII) treated with intraperitoneal (i.p.) adenosine 5′‐triphosphate (ATP) were studied in vitro, and in vivo in both C3H and nu/nu mice. In vivo daily ATP treatments caused a small dose‐dependent reduction in the total neovascular lumen area and thallium washout. There was an associated reduction in tumor volume doubling time but a similar growth rate reduction was also seen in vitro where flow has no impact. Daily ATP treatments at the maximally tolerated dose (2 mmol/kg i.p.) did not significantly affect the pH nuclear magnetic resonance or the phosphocreatine/inorganic phosphate (PCr/Pi), βATP/Pi, or phosphomonoester (PME)/ βATP ratios. The acute systemic physiological effects of i.p. ATP were mild, consisting of a transient reduction in skin laser Doppler flow and mean arterial pressure. Systemic toxicities of ATP given as daily boluses at doses capable of producing significant growth retardation of FSaII tumors were transient. Our results are most consistent with the hypothesis that the growth retarding effects of ATP are primarily a result of a decreased proliferation rather than tumor cytotoxicity or systemic pathophysiology. The main toxicity of ATP at active dose levels is cardiovascular. ATP might be useful as a biological modifier of chemotherapy or radiation. © 1994 Wiley‐Liss, IncThis article is a US Government work and, as such, is in the public domain in the United Stales of America.
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Differential modulation of radiosensitivity following induction of cis‐platinum resistance in radiation‐sensitive and radiation‐resistant human tumor cells
Authors: Britten Richard A. , Warenius Hilmar M. , Carraway Alma V. , Murray David 
Published: February 2007

AbstractThe effect of the induction of cis‐platinum resistance on clinically relevant radiosensitivity, i.e., surviving fraction at 2 Gy (SF2), has been studied in 8 human tumor cell lines with SF2 values ranging from 0.32 to 0.70. The induction of cis‐platinum resistance was accompanied by alterations in radiosensitivity in all of the cell lines studied; however, there was no relationship between the degree of induced cis‐platinum resistance (which varied from 1.5‐ to 7‐fold) and the concomitant change in radiosensitivity. The extent (up to 1.55‐fold) and the direction of the modulation of radiosensitivity were inversely related (P < 0.01) to the inherent radiosensitivity of the parental line prior to the induction of cis‐platinum resistance. cis‐Platinum resistance was associated with the radio‐protection of initially radiosensitive cells and the radiosensitization of inherently radioresistant phenotypes. If this inverse relationship between the initial radiosensitivity of the parental line and the cis‐platinum‐mediated alteration in SF2 values occurs in the clinical setting it could have important ramifications for treatment outcome. Clearly if patients with tumors that are ordinarily radioresponsive were to receive neo‐adjuvant cis‐platinum‐based chemotherapy, there could be a significant reduction in radioresponsiveness. On the other hand, there may be some advantage in the use of cis‐platinum‐based chemotherapy followed by radiotherapy in typically radioresistant tumors. © Wiley‐Liss, Inc.
Brain tumor uptake of thallium‐201 from the cerebrospinal fluid compartment: A preliminary study of uptake and diffusion dynamics
Authors: Rubertone Joseph A. , Woo David V. , Emrich Jacqueline G. , Brady Luther W. 
Published: February 2007

AbstractThallium‐201 (201Tl) has become a potent diagnostic tool for imaging brain tumors. Since intrathecal injections of 201T1 result in high resolution images of normal brain, experiments were designed to study tumor uptake and diffusion of 201T1 subsequent to cerebrospinal fluid (CSF) injection. A1SA5 astrocytoma cells were injected into the rat caudoputamen. Two weeks post‐implantation, rats received lateral ventricle injections of 201T1. Deeply anesthetized rats were perfused with 4.0% buffered formalin. Brains were removed, sectioned, and processed for autoradiography. Autoradiographs (ARGs) were developed and mounted sections were stained with hematoxylin and eosin. ARGs reveal a high degree of tumor to background resolution. Small tumor processes and cellular metastasis parallel to fiber tracts are readily visualized. 201TI labeling in areas of no apparent histologic disease, immediately surrounding and caudal to tumors, is suggestive of uptake by cells undergoing transformation. These studies are the first to demonstrate tumor uptake subsequent to 201T1 CSF injection and provide insights into the movement of 201T1 through tumor and adjacent neuropil. © Wiley‐Liss, Inc.
The doubling time of human tumours during radiotherapy: An analysis based on comparison between clinical and in vitro tumour cell radioresponsiveness
Authors: Brodin O. 
Published: February 2007

AbstractA correspondence between the effect of 2 Gy in vitro for human tumour cell lines and the clinical effect of radiotherapy of the corresponding tumours has earlier been described. In this analysis data on surviving fraction (SF) in vitro have been applied to clinical studies in a predictive model similar to the linear‐quadratic model for the calculation of isodoses. In addition, a proliferation factor describing exponential growth has been included. Different proliferation rates have been tested and the predicted probabilities for local control have been compared with the clinical local control rates of respective studies. The best correspondence between predicted and clinical results were found for a potential doubling time of 2–3 days during a whole treatment course, even for radiotherapy courses shorter than 3–4 weeks. The possible impact of hypoxia is discussed. © Wiley‐Liss, Inc.
DNA supercoiling and repair in peripheral lymphocytes as a measure of acute radiation response after radiotherapy
Authors: Rosemann Michael , Schulze Brigitte , Abel Helmut 
Published: February 2007

AbstractDNA supercoiling density and incision kinetics during ultraviolet (UV) excision repair hav been measured in lymphocytes from 20 cancer patients and 17 healthy donors. Nucleoid sedimentation was used, which allows the sensitive detection of both DNA damage and alterations in chromatin structure. The release of DNA supercoiling after ethidium bromide intercalation and the kinetics of the incision step following UV irradiation were compared in lymphocytes derived from cancer patients and those from normal donors. The classification into lymphocytes with normal or reduced repair and normal or altered supercoiling, respectively, revealed that reduced repair as well as altered chromatin structure occurred more frequently in lymphocytes derived from patients (40% and 85%, respectively) than in those from healthy donors (35% and 23%, respectively). Even more striking was the simultaneous occurrence of both characteristics in tumor patients: in 34% of all cases reduced repair was associated with altered supercoiling density, whereas among healthy donors this association occurred in only 18% of all cases. Supercoiling density may be related to functional integrity of lymphocytes and repair capacity to recovery after radiation damage. Since both parameters are important for the radiation response of normal tissue, we consider these measurements a potential prognostic assay aimed at reducing acute reaction of the normal tissue. © Wiley‐Liss, Inc.
Radiation response and other characteristics of the 9l rat glioma grown as an epigastric tissue isolate
Authors: Evans Sydney M. , Koch Cameron J. 
Published: February 2007

AbstractWe studied the 9L tumor as a tissue isolated epigastric implant. Data supporting its applicability to this site, including tumor blood flow, glucose metabolism, plating efficiency, radiation response, and histophatologic appearance, are described. Implants were performed on 175‐250 g male Fischer rats by tying 2–3 mm3 pieces of tumor onto the proximal segment of the epigastric branch of the femoral artery. Characteristics of the model include recovered cell yields of 6.1 ± 4.2 × 107 cells/g; 19–23% plating efficiency; 5% relative surviving fraction at 19.3 and 27.6 Gy in air breathing and euthanized rats, respectively; mean glucose utilization rate of 229 ± 182 nmol/min/g; and tumor blood flow of 1.9–21.3 ml/min/100 g in 0.4–303 g tumors. These characteristics, for the first time, provide a common framework for simultaneous evaluation of tumor metabolism and radiation response. © Wiley‐Liss, Inc.
Chemoradiotherapy for anal carcinoma: What is the optimal radiation dose?
Authors: Fung Claire Y. , Willett Christopher G. , Efird Jimmy T. , Shellito Paul C. , Kaufman Donald S. 
Published: February 2007

AbstractA dose‐response analysis was undertaken in a group of patients with clinically node‐negative carcinoma of the anal canal treated with a sphincter‐sparing approach. Twenty‐three patients underwent biopsy of the primary tumor, followed by concurrent radiation and chemotherapy. The chemotherapy regimen of 5‐fluorouracil and mitomycin C and radiation technique were uniform in all patients. The total radiation dose, given in daily fractions of 180–200 cGy, was escalated over the years as an institutional policy. The total radiation dose was ≤5,200 cGy (mean 4,550 cGy) in 11 cases treated before September 1989 and >5,200 cGy (mean 5,572 cGy) in 12 cases treated subsequently. The 3‐year actuarial local control rates were 53% vs. 100% for the low vs. high dose groups, respectively (P = 0.015). The 3‐year actuarial overall survival rates were 82% vs. 100% in the 2 groups, respectively. No increase in late toxicity in the high dose group has been observed compared to the low dose group. These results, albeit based on limited patient numbers, suggest that total radiation dose is an important determinant of long‐term tumor control in patients with localized anal canal carcinoma. A total radiation dose of approximately 5,500 cGy has led to excellent tumor control and sphincter function. © Wiley‐Liss, Inc.
Increased radioresistance at clinical doses: Investigations from the survival perspective
Authors: Skov Kirsten , Marples Brian 
Published: February 2007

AbstractStandard models of radiation action do not accurately describe survival at low clinically relevant X‐ray doses. This was made evident by survival experiments using methods which assayed a precise number of cells. At extremely low doses of X‐rays (<<0.5 Gy) a hypersensitive response exists which results in an inflection in the survival curve describing the response of many cell lines. In the case of sparsely ionizing radiations, this sensitive response is typically followed by an increased resistant response with a further increment in dose, which varies with cell line. This phenomenon may be explained as resistance induced by small doses of radiation. The background of this clinically interesting effect is described, as are methods to measure survival up to doses of ∼4 Gy. Evidence for increased radioresistance is reviewed and then briefly compared with the adaptive response which has been well studied in lymphocytes at still lower doses using endpoints other than survival. Possible implications for clinical treatment are considered. In addition, we summarize our recent studies directed toward understanding the molecular basis of the increased radioresistance using modifiers of radiation response, repair‐deficient cell lines, and radiation of different linear energy transfer (LET). While DNA damage appears to be a possible trigger for the response, the natures of the exact lesion(s) and the molecular response(s) which result remain unknown. © Wiley‐Liss, Inc.