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Brian D Ross - One of the best experts on this subject based on the ideXlab platform.
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diffusion magnetic resonance imaging an early surrogate marker of therapeutic efficacy in brain tumors
Journal of the National Cancer Institute, 2000Co-Authors: Thomas L Chenevert, Lauren D Stegman, Jeremy M G Taylor, Patricia L Robertson, Harry S Greenberg, Alnawaz Rehemtulla, Brian D RossAbstract:Background: A surrogate marker for treatment response that can be observed earlier than comparison of sequential magnetic resonance imaging (MRI) scans, which depends on relatively slow changes in tumor volume, may improve survival of brain tumor patients by providing more time for secondary therapeutic interventions. Previous studies in animals with the use of diffusion MRI revealed rapid changes in tumor water diffusion values after successful therapeutic intervention. Methods: The present study examined the sensitivity of diffusion MRI measurements in orthotopic rat brain tumors derived from implanted rat 9L glioma Cells. The effectiveness of therapy for individual brain cancer patients was evaluated by measuring changes in tumor volume on neuroimaging studies conducted 6-8 weeks after the conclusion of a treatment cycle. Results: Diffusion MRI could detect water diffusion changes in orthotopic 9L gliomas after doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) that resulted in as little as 0.2 Log Cell Kill, a measure of tumor Cell death. Mean apparent diffusion coefficients in tumors were found to be correlated with and highly sensitive to changes in tumor Cellularity (r = .78; two-sided P = .041). The feasibility of serial diffusion MRI in the clinical management of primary brain tumor patients was also demonstrated. Increased diffusion values could be detected in human brain tumors shortly after treatment initiation. The magnitude of the diffusion changes corresponded with clinical outcome. Conclusions: These results suggest that diffusion MRI will provide an early surrogate marker for quantification of treatment response in patients with brain tumors.
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monitoring early response of experimental brain tumors to therapy using diffusion magnetic resonance imaging
Clinical Cancer Research, 1997Co-Authors: Thomas L Chenevert, Paul E Mckeever, Brian D RossAbstract:Quantitative magnetic resonance imaging was performed to evaluate water diffusion and relaxation times, T1 and T2, as potential therapeutic response indicators for brain tumors using the intracranial 9L brain tumor model. Measurements were localized to a column that intersected tumor and contralateral brain and were repeated at 2-day intervals before and following a single injection of 1,3-bis(2-chloroethyl)-1-nitrosourea (13.3 mg/kg). Tumor growth was measured using T2-weighted magnetic resonance imaging to determine the volumetric tumor doubling time (Td) before (Td = 64 +/- 13 h, mean +/- SD, n = 16) and after (Td = 75 +/- 9 h, n = 4) treatment during exponential regrowth. Apparent diffusion coefficient of untreated tumors was independent of tumor volume or growth time, whereas relaxation times increased during early tumor growth. Diffusion displayed the strongest treatment effect and increased before tumor regression by 55% 6-8 days following treatment. Changes in relaxation times were also significant with increases of 16% for T1 and 27% for T2. Diffusion and relaxation times returned to pretreatment levels by 12 days after treatment. HistoLogical examination supports the model that the observed increase in diffusion reflects an increase of extraCellular space following treatment. Furthermore, the subsequent apparent diffusion coefficient decrease is a result of viable tumor Cells that repopulate this space at a rate dependent on the surviving tumor Cell fraction and recurrent tumor doubling time. Serial tumor volume measurements allowed determination of Log Cell Kill of 1.0 +/- 0.3 (n = 4). These results suggest that diffusion measurements are sensitive to therapy-induced changes in Cellular structure and may provide an early noninvasive indicator of treatment efficacy.
Thomas L Chenevert - One of the best experts on this subject based on the ideXlab platform.
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diffusion magnetic resonance imaging an early surrogate marker of therapeutic efficacy in brain tumors
Journal of the National Cancer Institute, 2000Co-Authors: Thomas L Chenevert, Lauren D Stegman, Jeremy M G Taylor, Patricia L Robertson, Harry S Greenberg, Alnawaz Rehemtulla, Brian D RossAbstract:Background: A surrogate marker for treatment response that can be observed earlier than comparison of sequential magnetic resonance imaging (MRI) scans, which depends on relatively slow changes in tumor volume, may improve survival of brain tumor patients by providing more time for secondary therapeutic interventions. Previous studies in animals with the use of diffusion MRI revealed rapid changes in tumor water diffusion values after successful therapeutic intervention. Methods: The present study examined the sensitivity of diffusion MRI measurements in orthotopic rat brain tumors derived from implanted rat 9L glioma Cells. The effectiveness of therapy for individual brain cancer patients was evaluated by measuring changes in tumor volume on neuroimaging studies conducted 6-8 weeks after the conclusion of a treatment cycle. Results: Diffusion MRI could detect water diffusion changes in orthotopic 9L gliomas after doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) that resulted in as little as 0.2 Log Cell Kill, a measure of tumor Cell death. Mean apparent diffusion coefficients in tumors were found to be correlated with and highly sensitive to changes in tumor Cellularity (r = .78; two-sided P = .041). The feasibility of serial diffusion MRI in the clinical management of primary brain tumor patients was also demonstrated. Increased diffusion values could be detected in human brain tumors shortly after treatment initiation. The magnitude of the diffusion changes corresponded with clinical outcome. Conclusions: These results suggest that diffusion MRI will provide an early surrogate marker for quantification of treatment response in patients with brain tumors.
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monitoring early response of experimental brain tumors to therapy using diffusion magnetic resonance imaging
Clinical Cancer Research, 1997Co-Authors: Thomas L Chenevert, Paul E Mckeever, Brian D RossAbstract:Quantitative magnetic resonance imaging was performed to evaluate water diffusion and relaxation times, T1 and T2, as potential therapeutic response indicators for brain tumors using the intracranial 9L brain tumor model. Measurements were localized to a column that intersected tumor and contralateral brain and were repeated at 2-day intervals before and following a single injection of 1,3-bis(2-chloroethyl)-1-nitrosourea (13.3 mg/kg). Tumor growth was measured using T2-weighted magnetic resonance imaging to determine the volumetric tumor doubling time (Td) before (Td = 64 +/- 13 h, mean +/- SD, n = 16) and after (Td = 75 +/- 9 h, n = 4) treatment during exponential regrowth. Apparent diffusion coefficient of untreated tumors was independent of tumor volume or growth time, whereas relaxation times increased during early tumor growth. Diffusion displayed the strongest treatment effect and increased before tumor regression by 55% 6-8 days following treatment. Changes in relaxation times were also significant with increases of 16% for T1 and 27% for T2. Diffusion and relaxation times returned to pretreatment levels by 12 days after treatment. HistoLogical examination supports the model that the observed increase in diffusion reflects an increase of extraCellular space following treatment. Furthermore, the subsequent apparent diffusion coefficient decrease is a result of viable tumor Cells that repopulate this space at a rate dependent on the surviving tumor Cell fraction and recurrent tumor doubling time. Serial tumor volume measurements allowed determination of Log Cell Kill of 1.0 +/- 0.3 (n = 4). These results suggest that diffusion measurements are sensitive to therapy-induced changes in Cellular structure and may provide an early noninvasive indicator of treatment efficacy.
Henry S Friedman - One of the best experts on this subject based on the ideXlab platform.
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repair analysis of 4 hydroperoxycyclophosphamide induced dna interstrand crosslinking in the c myc gene in 4 hydroperoxycyclophosphamide sensitive and resistant medulloblastoma Cell lines
Cancer Chemotherapy and Pharmacology, 1995Co-Authors: Qing Dong, Nancy Bullock, Francis Aliosman, Michael O Colvin, Darell D Bigner, Henry S FriedmanAbstract:Cyclophosphamide is one of the most active agents in the treatment of medulloblastoma. However, development of resistance to this alkylator frequently occurs and is the harbinger of tumor progression and death. In order to understand the biochemical basis of this resistance, we generated a panel of medulloblastoma Cell lines in our laboratory that were resistant to 4-hydroperoxycyclophosphamide (4-HC). Previously, we have shown that elevated levels of aldehyde dehydrogenase and glutathione mediate Cellular resistance to 4-HC. The present study was conducted to identify the third unknown mechanism mediating the resistance of Cell line D283 Med (4-HCR) to 4-HC, testing the hypothesis that this resistance is mediated by an increased repair of DNA interstrand crosslinks (ICLs). The doses of 4-HC that produced a one- and two-Log Cell Kill of D283 Med Cells were 25 and 50 μM, respectively, compared with values of 125 and 165 μM in D283 Med (4-HCR), the resistant Cell line. The formation and disappearance of 4-HC-induced DNA ICLs at the c-myc gene were subsequently studied by DNA denaturing/renaturing gel electrophoresis and Southern blot analysis. 4-HC-induced DNA ICLs in the c-myc gene exhibited a dose-dependent relationship. The percentage of the c-myc gene that was crosslinked was approximately 1–3% at a dose of 100 μM. More than 50% of the DNA crosslinking in D283 Med (4-HCR) Cells was removed by 6 h after drug treatment, whereas, in D283 Med Cells, more than 90% of the DNA crosslinking was still present at 6 h. These findings suggest that the increased repair of DNA ICLs in D283 Med (4-HCR) may contribute significantly to its resistance to 4-HC.
Donna S Shewach - One of the best experts on this subject based on the ideXlab platform.
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superior cytotoxicity with ganciclovir compared with acyclovir and 1 β d arabinofuranosylthymine in herpes simplex virus thymidine kinase expressing Cells a novel paradigm for Cell Killing
Cancer Research, 1998Co-Authors: Laura Z Rubsam, Beverly L Davidson, Donna S ShewachAbstract:Abstract Enzyme-prodrug therapy using ganciclovir and herpes simplex virus-thymidine kinase (HSV-TK) has demonstrated exCellent antitumor activity in many different types of malignant Cells. Previously, we noted that ganciclovir was substantially more cytotoxic than other HSV-TK substrates. Therefore, we embarked on a study to determine the basis for the superior cytotoxicity of ganciclovir. In U251tk human glioblastoma Cells that stably express HSV-TK, ganciclovir elicited a >4 Log Cell Kill instead of the ≤1.5 Log Cell Kill mediated by two other HSV-TK substrates, 1-β-d-arabinofuranosylthymine (araT) and acyclovir. Study of the metabolism of these drugs demonstrated that acyclovir was poorly phosphorylated to its active triphosphate with DNA incorporation below the limit of detection, which may explain the versus 1235 pmol/10 7 Cells, respectively), and the half-life for the triphosphate of ganciclovir was shorter than that of araT (terminal half-lives of 15 and 41 h, respectively). Incorporation of ganciclovir monophosphate into DNA was less than that of araT monophosphate, and both anaLogues were retained in DNA for ≥48 h. Thus, the superior cytotoxicity of ganciclovir was not due to enhanced metabolism to active forms. Highly cytotoxic concentrations of ganciclovir produced only weak inhibition of DNA synthesis. This allowed Cells to proceed through S and G 2 -M phases during and after drug exposure, resulting in a doubling of Cell number by 48 h after drug washout. As they attempted to progress through the Cell cycle a second time, ganciclovir-treated Cells accumulated in early S-phase and remained there until Cell death, suggesting that ganciclovir incorporation in the DNA template was important for cytotoxicity. In contrast, strong inhibition of DNA synthesis by araTTP prevented Cells from traversing the Cell cycle for at least 12 h after drug washout, when the active metabolite was largely degraded. araT-treated Cells were unable to divide for at least 72 h after drug exposure, at which point the surviving Cells displayed a normal Cell cycle distribution pattern. Based on the results presented here, we propose a novel paradigm in which the ability of ganciclovir to incorporate into DNA without inhibiting progression through S-phase, combined with high cytotoxicity for incorporated ganciclovir monophosphate, produces multiLog cytotoxicity.
Erik Fm Van Limbergen - One of the best experts on this subject based on the ideXlab platform.
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bioLogical effect of pulsed dose rate brachytherapy with stepping sources if short half times of repair are present in tissues
International Journal of Radiation Oncology Biology Physics, 1997Co-Authors: J F Fowler, Erik Fm Van LimbergenAbstract:Purpose: To explore the possible increase of radiation effect in tissues irradiated by pulsed brachytherapy (PDR) for local tissue dose rates between those “averaged over the whole pulse” and the instantaneous high dose rates close to the dwell positions. Increased effect is more likely for tissues with short half-times of repair of the order of a few minutes, similar to pulse durations. Methods and Materials: Calculations were done assuming the linear quadratic formula for radiation damage, in which only the dose-squared term is subject to exponential repair. The situation with two components of T,,, is addressed. A constant overall time of 140 h and a constant total dose of 70 Gy were assumed throughout, the continuous low dose rate of 0.5 Gy/b (CLDR) providing the unitary standard effects for each PDR condition. Effects of dose rates ranging from 4 Gy/h to 120 Gy/h (HDR at 2 Gy/min) were studied, covering the gap in an earlier publication. Four schedules were examined: doses per pulse of 0.5, 1, 1.5, and 2 Gy given at repetiton frequencies of 1,2, 3, and 4 h, respectively, each with a range of assumed half-times of repair of 4 min to 1.5 h. Results are presented for late-responding tissues, the differences from CLDR being two or three times greater than for early-responding tissues and most tumors. Results: Curves are presented relating the ratio of increased bioLogical effect (proportional to Log Cell Kill) calculated for PDR relative to CLDR. Ratios as high as 1.5 can be found for large doses per pulse (2 Gy) if the halftime of repair in tissues is as short as a few minutes. The major influences on effect are dose per pulse, half-time of repair in tissue, and-when T,,, is short--the instantaneous dose rate. Maximum ratios of PDRKLDR occur when the dose rate is such that pulse duration is approximately equal to T llz. As dose rate in the pulse is increased, a plateau of effect ls reached, for most Tl12s, above 10 to 20 Gy/h, which ls therefore radiobioLogically equivalent to the highest HDR. A stepping source of 1 curie carries a sphere of “HDR” of radius 20 mm with it in its track through tissue. High ratios of PDR/LDR effect can be avoided by keeping dose per pulse below 1 Gy. Conclusions: Therefore, about 75% of the total dose is delivered at HDR in a PDR implant of moderate volume, reducing to 40% as the source decays from 1 to 0.3 curies. Even so, restricting the dose per pulse to 0.5 or 0.6 Gy should avoid ratios of increased effect larger than about 10%. It appears likely that PDR delivered by stepping source might behave more like HDR than LDR, especially for tissues with a substantial component of repair of very short T,,,. 0 1997 Elsevler Science Inc.
