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Induction of tissue-type plasminogen activator by ionizing radiation in normal and cancer-prone human cells
Proceedings
of the 33rd Annual ASTRO
Meeting
147
62 3-D STATIC CONFORMAL TRIAL
RADIOTHERAPY:
PRELIMINARY
RESULTS
OF A PROSPECTIVE
CLINICAL
B. Emami, J.A. Purdy, J.M. Manolis, R.L. Gerber, W.B Harms, J.R. Simpson, F.J. Wippold, C.A. Perez Radiation Oncology Center, Washington University School of Medicine, St. Louis, MO Purpose: To study feasibility of large scale implementation of true 3D technologies in the treatment of prostate and head and neck cancer patients. Materials & Methods: Twenty patients (10 prostate and 10 head and neck) were prospectively planned according to our standard treatment policies using traditional two-dimensional treatment planning methodologies without access to full 3-D volumetric information. Concurrently, these patients were CT scanned obtaining full volumetric image data and planned using 3-D tools e.g., beams-eye-view, room-view or observer’s_eye-view, multiple noncoplanar beams, dose-volume histograms, dose surfaces, etc. The 2D plans and 3D plans were performed independently. The results were quantitatively compared using dose-volume hi&o&Tarns and dose surface displays and patients were treated according to the plan judged best when feasible. Results: For prostate patients, better tumor coverage is possible with 3-D plans. However, there is a discrepancv between 3-D target volumes determined from CT versus traditional treatment volumes determined by experikncea raiation oncologist. In addition, an average of 14% of the bladder and rectum volumes can be snared from hieh dose radiotherapy. For head and n&k patie&, the results were variable. There were three patieits in which complete tumor coverage and limiting of critical structures below tolerance level was not possible with 2-D planning but was achieved with 3-D treatment planning. Whereas in others no significant improvement was obtained using 3-D of volume definitions between 2-D and 3planning. The reasons for the latter is thought to be due to: (1) discrepancy D methodologies; (2) use of parallel-opposed beams (2-D technique) as initial part of 3-D treatment planning and (3) unfamiliarity with optimal non-coplanar beam arrangements. The ability ,to use non-coplanar fields in the two sites constituted an advantage of 3D planning. This Conclusion: capability led to better tumor coverage and reduced dose to critical normal tissues. However, this advantage was coupled with greater treatment complexity.
63 INDUCTION OF TISSUE-TYPE PLASMINOGEN ACTIVATOR BY IONIZING RADIATION IN NORMAL AND CANCER-PRONE HUMAN CELLS. Supported by an ASTRO Research Fellowship 1990-1991. Nina Fulcunaga and David Boothman Department of Radiation Oncology, Division of Cancer Biology, University of Michigan Medical Center, Ann Arbor, MI 481090582. We have previously described the synthesis of X-Ray-Induced Proteins (XIPs) in human melanoma (Ul-Mel) cells using two-dimensional gel electrophoresis (Boothman et al., Cancer Research 49: 2871-2879, 1990). We are currently in the process of producing a cDNA library from normal and cancer-prone human cells and will screen them using subtractive and/or differential hybridization techniques to select for medium to low abundance induced mRNA transcripts. Complementary DNA (cDNA) libraries from Ul-Mel cells were screened via differential hybridization and revealed one clone with >95% DNA sequence homology to human tissue-plasminogen activator (t-PA). Normal human fibroblast cells (i.e., GM2936B, IMR-90, and GM 2907A) and cancer-prone fibroblast cells (i.e., Fanconi’s Anemia, Bloom’s Syndrome, and Ataxia Telengectasia) induced t-PA at 6 and 12 hours following ionizing radiation. Induced t-PA enzymatic activities following ionizing radiation were blocked by cyclohexamide or actinomycin D treatments. Human cancer-prone cells demonstrated a greater induction of t-PA compared to normal human fibroblast cells. t-PA enzymatic activity was induced over 20-fold for the Ataxia Telengectasia cells, over 16-fold for Bloom’s Svndrome cells and over g-fold for the Fanconi’s Anemia cells. as cornoared to nonnd human fib&blasts. The induction of t-PA mRNA levels and activities for normal human cells were morethan 50-ibid less than that observed with Ul-Mel cells given equitoxic doses of ionizing radiation. The differential expression of t-PA in normal and cancer-prone cells as compared totumorsmay be utilized for therapeutic benefits. The higher iiduction of an intracellular protease in human cancer-prone cells is reminiscent of an “SOS”-like response observed in yeast and bacteria.
of the 33rd Annual ASTRO
Meeting
147
62 3-D STATIC CONFORMAL TRIAL
RADIOTHERAPY:
PRELIMINARY
RESULTS
OF A PROSPECTIVE
CLINICAL
B. Emami, J.A. Purdy, J.M. Manolis, R.L. Gerber, W.B Harms, J.R. Simpson, F.J. Wippold, C.A. Perez Radiation Oncology Center, Washington University School of Medicine, St. Louis, MO Purpose: To study feasibility of large scale implementation of true 3D technologies in the treatment of prostate and head and neck cancer patients. Materials & Methods: Twenty patients (10 prostate and 10 head and neck) were prospectively planned according to our standard treatment policies using traditional two-dimensional treatment planning methodologies without access to full 3-D volumetric information. Concurrently, these patients were CT scanned obtaining full volumetric image data and planned using 3-D tools e.g., beams-eye-view, room-view or observer’s_eye-view, multiple noncoplanar beams, dose-volume histograms, dose surfaces, etc. The 2D plans and 3D plans were performed independently. The results were quantitatively compared using dose-volume hi&o&Tarns and dose surface displays and patients were treated according to the plan judged best when feasible. Results: For prostate patients, better tumor coverage is possible with 3-D plans. However, there is a discrepancv between 3-D target volumes determined from CT versus traditional treatment volumes determined by experikncea raiation oncologist. In addition, an average of 14% of the bladder and rectum volumes can be snared from hieh dose radiotherapy. For head and n&k patie&, the results were variable. There were three patieits in which complete tumor coverage and limiting of critical structures below tolerance level was not possible with 2-D planning but was achieved with 3-D treatment planning. Whereas in others no significant improvement was obtained using 3-D of volume definitions between 2-D and 3planning. The reasons for the latter is thought to be due to: (1) discrepancy D methodologies; (2) use of parallel-opposed beams (2-D technique) as initial part of 3-D treatment planning and (3) unfamiliarity with optimal non-coplanar beam arrangements. The ability ,to use non-coplanar fields in the two sites constituted an advantage of 3D planning. This Conclusion: capability led to better tumor coverage and reduced dose to critical normal tissues. However, this advantage was coupled with greater treatment complexity.
63 INDUCTION OF TISSUE-TYPE PLASMINOGEN ACTIVATOR BY IONIZING RADIATION IN NORMAL AND CANCER-PRONE HUMAN CELLS. Supported by an ASTRO Research Fellowship 1990-1991. Nina Fulcunaga and David Boothman Department of Radiation Oncology, Division of Cancer Biology, University of Michigan Medical Center, Ann Arbor, MI 481090582. We have previously described the synthesis of X-Ray-Induced Proteins (XIPs) in human melanoma (Ul-Mel) cells using two-dimensional gel electrophoresis (Boothman et al., Cancer Research 49: 2871-2879, 1990). We are currently in the process of producing a cDNA library from normal and cancer-prone human cells and will screen them using subtractive and/or differential hybridization techniques to select for medium to low abundance induced mRNA transcripts. Complementary DNA (cDNA) libraries from Ul-Mel cells were screened via differential hybridization and revealed one clone with >95% DNA sequence homology to human tissue-plasminogen activator (t-PA). Normal human fibroblast cells (i.e., GM2936B, IMR-90, and GM 2907A) and cancer-prone fibroblast cells (i.e., Fanconi’s Anemia, Bloom’s Syndrome, and Ataxia Telengectasia) induced t-PA at 6 and 12 hours following ionizing radiation. Induced t-PA enzymatic activities following ionizing radiation were blocked by cyclohexamide or actinomycin D treatments. Human cancer-prone cells demonstrated a greater induction of t-PA compared to normal human fibroblast cells. t-PA enzymatic activity was induced over 20-fold for the Ataxia Telengectasia cells, over 16-fold for Bloom’s Svndrome cells and over g-fold for the Fanconi’s Anemia cells. as cornoared to nonnd human fib&blasts. The induction of t-PA mRNA levels and activities for normal human cells were morethan 50-ibid less than that observed with Ul-Mel cells given equitoxic doses of ionizing radiation. The differential expression of t-PA in normal and cancer-prone cells as compared totumorsmay be utilized for therapeutic benefits. The higher iiduction of an intracellular protease in human cancer-prone cells is reminiscent of an “SOS”-like response observed in yeast and bacteria.