Combinations of Ionizing Radiation and Other Sensitizing Agents

  • Minesh P. Mehta
Part of the Medical Radiology book series (MEDRAD)


Brain Metastasis Clin Oncol Radiat Oncol Biol Phys Glioblastoma Multiforme MGMT Promoter Methylation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abraham DJ, Peascoe RA, Randad RS, Panikker J (1992) X-ray diffraction study of di and tetra-ligated T-state hemoglobin from high salt crystals. J Mol Biol 227:480–492PubMedCrossRefGoogle Scholar
  2. Andrews DW, Scott C, Sperduto PW et al (2004) Phase III randomized trial comparing whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: results of the RTOG 9508 trial. Lancet 363:1665–1673PubMedCrossRefGoogle Scholar
  3. Antonadou D, Paraskevaidis M, Sarris G et al (2002a) Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 20:3644–3650PubMedCrossRefGoogle Scholar
  4. Antonadou D, Coliarakis N, Paraskevaidis M et al (2002b) Whole brain radiotherapy alone or in combination with temozolomide for brain metastases. A phase III study (Abstract). Int J Radiat Oncol Biol Phys 54(Suppl):93–94CrossRefGoogle Scholar
  5. Athanassiou H, Synodinou M, Maragoudakis E et al (2005) Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme. J Clin Oncol 23:2372–2377PubMedCrossRefGoogle Scholar
  6. Biaglow JE, Miller RA (2005) The thioredoxin reductase/thioredoxin system: novel redox targets for cancer therapy. Cancer Biol Ther 4:6–13PubMedCrossRefGoogle Scholar
  7. Calabrese CR, Almassy R, Barton S et al (2004) Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst 96:56–67PubMedCrossRefGoogle Scholar
  8. Carde P, Timmerman B, Koprowski D et al (1998) Gadolinium-Texaphyrin (Gd-Tex) radiation sensitizer: improved survival in a phase IB/II trial in patients with brain metastases (Abstract). Proc Am Soc Clin Oncol 17:379aGoogle Scholar
  9. Carde P, Timmerman R, Mehta MP et al (2001) Multicenter phase Ib/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases. J Clin Oncol 19:2074–2083PubMedGoogle Scholar
  10. Chinnasamy N, Rafferty JA, Hickson I et al (1997) O6-benzyl-guanine potentiates the in vivo toxicity and clastogenicity of temozolomide and BCNU in mouse bone marrow. Blood 89:1566–1573PubMedGoogle Scholar
  11. Combs SE, Gutwein S, Schulz-Ertner D et al (2004) Temozolomide combined with radiation as first-line treatment in primary glioblastoma multiforme: phase I/II study (Abstract). J Clin Oncol 22(14S):1531Google Scholar
  12. Curtin NJ, Wang LZ, Yiakouvaki A et al (2004) Novel poly(ADP-ribose) polymerase-1 inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair-deficient cells. Clin Cancer Res 10:881–889PubMedCrossRefGoogle Scholar
  13. Denny BJ, Wheelhouse RT, Stevens MF et al (1994) NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry 33:9045–9051PubMedCrossRefGoogle Scholar
  14. Dolan ME, Stine L, Mitchell RB et al (1990) Modulation of mammalian O6-alkylguanine-DNA alkyltransferase in vivo by O6-benzylguanine and its effect on the sensitivity of a human glioma tumor to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea. Cancer Commun 2:371–377PubMedGoogle Scholar
  15. Donnelly ET, Liu Y, Paul TK, Rockwell S (2005) Effects of motexafin gadolinium on DNA damage and X-ray-induced DNA damage repair, as assessed by the Comet assay. Int J Radiat Oncol Biol Phys 62:1176–1186PubMedCrossRefGoogle Scholar
  16. Esteller M, Herman JG (2004) Generating mutations but providing chemosensitivity: the role of O6-methylgauanine DNA methyltransferase in human cancer. Oncogene 23:1–8PubMedCrossRefGoogle Scholar
  17. Estellar M, Hamilton SR, Burger PC et al (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797Google Scholar
  18. Esteller M, Garcia-Foncillas J, Andion E et al (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354PubMedCrossRefGoogle Scholar
  19. Evans RG, Kimler BF, Morantz RA et al (1990) A phase I/II study of the use of Fluosol as an adjuvant to radiation therapy in the treatment of primary high-grade brain tumors. Int J Radiat Oncol Biol Phys 19:415–420PubMedGoogle Scholar
  20. Ford J, Seiferheld W, Mehta M et al (2003) Comparison of survival of patients in the phase I study of motexafin gadolinium (MGd) with radiation therapy (RT) for glioblastoma multiforme (GBM), with a matched cohort of patients from the RTOG RPA glioma data base (Abstract). Proc Am Soc Clin Oncol 22:106Google Scholar
  21. Friedman HS, McLendon RE, Kerby T et al (1998) DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 16:3851–3857PubMedGoogle Scholar
  22. Furonaka O, Takeshima Y, Awaya H et al (2005) Aberrant methylation and loss of expression of O-methylguanine-DNA methyltransferase in pulmonary squamous cell carcinoma and adenocarcinoma. Pathol Int 55:303–309PubMedCrossRefGoogle Scholar
  23. Hegi ME, Diserens AC, Godard S et al (2004) Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:1871–1874PubMedCrossRefGoogle Scholar
  24. Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003PubMedCrossRefGoogle Scholar
  25. Jaeckle KA, Eyre HJ, Townsend JJ et al (1998) Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study. J Clin Oncol 16:3310–3315PubMedGoogle Scholar
  26. Karran P, Marinus MG (1982) Mismatch correction at O6-methylguanine residues in E. coli DNA. Nature 296:868–869PubMedCrossRefGoogle Scholar
  27. Kesslering C, Renschler M, Vanel D et al (1998) Selective uptake and retention of the radiation sensitizer Gadolinium Texaphyrin (Gd-Tex) in tumors demonstrated by MRI in phase I and phase II clinical trials (Abstract). Int J Radiat Oncol Biol Phys 42:263CrossRefGoogle Scholar
  28. Lapidus RG, Tentori L, Graziani G et al (2005) Oral administration of PARP inhibitor GPI 18180 increases the anti-tumor activity of temozolomide against intracranial melanoma in mice (Abstract). J Clin Oncol 23(16S):3136Google Scholar
  29. Lee SW, Fraass BA, Marsh LH et al (1999) Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys 43:79–88PubMedCrossRefGoogle Scholar
  30. Liu L, Markowitz S, Gerson SL (1996) Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl)nitrosourea. Cancer Res 56:5375–5379PubMedGoogle Scholar
  31. Ludlum DB (1990) DNA alkylation by the haloethylnitrosoureas: nature of modifications produced and their enzymatic repair or removal. Mutat Res 233:117–126PubMedGoogle Scholar
  32. Magda D, Lepp C, Gerasimchuk N et al (2001) Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species. Int J Radiat Oncol Biol Phys 51:1025–1036PubMedCrossRefGoogle Scholar
  33. Manon R, Hui S, Chinnaiyan P, et al (2004) The impact of mid-treatment MRI on defining boost volumes in the radiation treatment of glioblastoma multiforme. Technol Cancer Res Treat 3:303–307PubMedGoogle Scholar
  34. McGinn CJ, Shewach DS, Lawrence TS (1996) Radiosensitizing nucleosides. J Natl Cancer Inst 88:1193–1203PubMedGoogle Scholar
  35. Mehta MP, Suh JH (2004) Novel radiosensitizers for tumors of the central nervous system. Curr Opin Invest Drugs 5:1284–1291Google Scholar
  36. Mehta M, Ford J, Carde P et al (1999) Gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer for primary and metastatic brain tumors (Abstract). Neuro-Oncol 1:540Google Scholar
  37. Mehta MP, Seiferheld W, Delrowe J et al (2001a) Glioblastoma multiforme: the phase II RTOG Experience (Abstract). Neuro-Oncol 3:350Google Scholar
  38. Mehta M, Ames M, Reid J et al (2001b) Phase I study of Motexafin-Gadolinium (M-Gd) as a radiosensitizer for pediatric intrinsic pontine glioma (BSG): a Children’s Oncology Group study (Abstract). Proc Am Soc Clin Oncol 20:62aGoogle Scholar
  39. Mehta MP, Shapiro WR, Glantz MJ et al (2002) Lead-in phase to randomized trial of motexafin gadolinium and whole-brain radiation for patients with brain metastases: centralized assessment of magnetic resonance imaging, neurocognitive, and neurologic end points. J Clin Oncol 20:3445–3453PubMedCrossRefGoogle Scholar
  40. Mehta MP, Rodrigus P, Terhaard CHJ et al (2003) Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole brain radiation therapy in brain metastases. J Clin Oncol 21:2529–2536PubMedCrossRefGoogle Scholar
  41. Mehta M, Ford JM, Suh J, Phan S (2004) Cumulative dose of motexafin gadolinium and survival in newly diagnosed glioblastoma multiforme (Abstract). Neuro-Oncol 6:378Google Scholar
  42. Miller RA, Woodburn K, Fan Q et al (1999) In vivo animal studies with gadolinium (III) texaphyrin as a radiation enhancer. Int J Radiat Oncol Biol Phys 45:981–989PubMedCrossRefGoogle Scholar
  43. Miller RA, Woodburn KW, Fan Q et al (2001) Motexafin gadolinium: a redox active drug that enhances the efficacy of bleomycin and doxorubicin. Clin Cancer Res 7:3215–3221PubMedGoogle Scholar
  44. Mintz AH, Kestle J, Rathbone MP et al (1996) A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 78:1470–1476PubMedCrossRefGoogle Scholar
  45. Noordijk EM, Vecht CJ, Haaxma-Reiche J et al (1994) The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 29:711–717PubMedGoogle Scholar
  46. Patchell RA, Tibbs PA, Walsh JW et al (1990) A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494–500PubMedCrossRefGoogle Scholar
  47. Patel M, McCully C, Godwin K et al (2003) Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates. J Neurooncol 61:203–207PubMedCrossRefGoogle Scholar
  48. Patel RR, Tomé WA, Mehta MP (2004) Radiation therapy for CNS tumors. In: Principles of neurosurgery, 2nd edn. Rengachary S and Ellenbogen R (eds) Mosby, St. Louis, pp 719–728Google Scholar
  49. Paz MF, Yaya-Tur R, Rojas-Marcos I et al (2004) CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res 10:4933–4938PubMedCrossRefGoogle Scholar
  50. Pegg AE, Wiest L, Foote RS et al (1983) Purification and properties of O6-methylguanine-DNA transmethylase from rat liver. J Biol Chem 258:2327–2333PubMedGoogle Scholar
  51. Pieper RO (1997) Understanding and manipulating O6-methylguanine-DNA methyltransferase expression. Pharmacol Ther 74:285–297PubMedCrossRefGoogle Scholar
  52. Phillips TL, Scott CB, Leibel SA et al (1995) Results of a randomized comparison of radiotherapy and bromodeoxyuridine with radiotherapy alone for brain metastases: report of RTOG trial 89-05. Int J Radiat Oncol Biol Phys 33:339–348PubMedCrossRefGoogle Scholar
  53. Plummer R, Middleton M, Wilson R et al (2005) First in human phase I trial of the PARP inhibitory AG-014699 with temozolomide (TMZ) in patients with advanced solid tumors (Abstract). J Clin Oncol 23(16S):3065Google Scholar
  54. Prados MD, Scott C, Sandler H et al (1999) A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404. Int J Radiat Oncol Biol Phys 45:1109–1115PubMedCrossRefGoogle Scholar
  55. Qian XC, Brent TP (1997) Methylation hot spots in the 5’ flanking region denote silencing of the O6-methylguanine-DNA methyltransferase gene. Cancer Res 57:3672–3677PubMedGoogle Scholar
  56. Reid JM, Stevens DC, Rubin J et al (1997) Pharmacokinetics of 3-methyl-(triazen-1-yl)imidazole-4-carboximide following administration of temozolomide to patients with advanced cancer. Clin Cancer Res 3:2393–2398PubMedGoogle Scholar
  57. Rockwell S, Donnelly ET, Liu Y, Tang LQ (2002) Preliminary studies of the effects of gadolinium texaphyrin on the growth and radiosensitivity of EMT6 cells in vitro. Int J Radiat Oncol Biol Phys 54:536–541PubMedCrossRefGoogle Scholar
  58. Rodrigus P (2003) Motexafin gadolinium: a possible new radiosensitizer. Exp Opinion Invest Drugs 12:1205–1210CrossRefGoogle Scholar
  59. Roos W, Baumgartner M, Kaina B (2004) Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1. Oncogene 23:359–367PubMedCrossRefGoogle Scholar
  60. Rosenthal DI, Becerra CR, Toto RD et al (2000) Reversible renal toxicity resulting from high single doses of the new radiosensitizer gadolinium texaphyrin. Am J Clin Oncol 23:593–598PubMedCrossRefGoogle Scholar
  61. Schold SC Jr, Kokkinakis DM, Chang SM et al (2004) O6-benzylguanine suppression of O6-alkylguanine-DNA alkyltransferase in anaplastic gliomas. Neuro-Oncol 6:28–32PubMedCrossRefGoogle Scholar
  62. Siena S, Landonio G, Baietta E et al (2003) Multicenter phase II study of temozolomide therapy for brain metastasis in patients with malignant melanoma, breast cancer, and non-small cell lung cancer (Abstract). Proc Am Soc Clin Oncol:102Google Scholar
  63. Silber JR, Blank A, Bobola MS et al (1999) O6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy. Clin Cancer Res 5:807–814PubMedGoogle Scholar
  64. Srivenugopal KS, Shou J, Mullapudi SR et al (2001) Enforced expression of wild-type p53 curtails the transcription of the O(6)-methylguanine-DNA methyltransferase gene in human tumor cells and enhances their sensitivity to alkylating agents. Clin Cancer Res 7:1398–1409PubMedGoogle Scholar
  65. Stasio G de, Casalbore P, Gilbert B et al (2001) Gadolinium in human glioblastoma cells for gadolinium neutron capture therapy (GdNCT). Cancer Res 61:4272–4277PubMedGoogle Scholar
  66. Stasio G de, Rajesh D, Casalbore P et al (2005) Are gadolinium contrast agents suitable for gadolinium neutron capture therapy? Neuro Res 27:387–398CrossRefGoogle Scholar
  67. Stupp R, Dietrich PY, Ostermann Kraljevic S et al (2002) Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20:1375–1382PubMedCrossRefGoogle Scholar
  68. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  69. Suh J, Chang E, Timmerman R et al (2002) Phase II trial of motexafin gadolinium (MGd, Xcytrin) and cranial radiation in newly diagnosed glioblastoma multiforme (Abstract). Proc Am Soc Clin Oncol 21:74bGoogle Scholar
  70. Tentori L, Portarena I, Bonmassar E, Graziani G (2001) Combined effects of adenovirus-mediated wild-type p53 transduction, temozolomide and poly (ADP-ribose) polymerase inhibitor in mismatch repair deficient and non-proliferating tumor cells. Cell Death Differ 8:457–469PubMedCrossRefGoogle Scholar
  71. Tentori L, Portarena I, Graziani G (2002) Potential clinical applications of poly(ADP-ribose) polymerase (PARP) inhibitors. Pharmacol Res 45:73–85PubMedCrossRefGoogle Scholar
  72. Tolcher AW, Gerson SL, Denis et al (2003) Marked inactivation of O6-alkylguanineDNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 88:1004–1011PubMedCrossRefGoogle Scholar
  73. van Rijn J, Heimans JJ, van den Berg J et al (2000) Survival of human glioma cells treated with various combination of temozolomide and X-rays. Int J Radiat Oncol Biol Phys 47:779–784PubMedCrossRefGoogle Scholar
  74. Verger E, Gil M, Yaya R et al (2003) Concomitant temozolomide and whole brain radiotherapy in patients with brain metastases: randomized multicentric phase II study (Abstract). Proc Am Soc Clin Oncol 22:101Google Scholar
  75. Walker MD, Strike TA, Sheline GE (1979) An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5:1725–1731PubMedGoogle Scholar
  76. Wallner KE, Galicich JH, Krol G et al (1989) Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16:1405–1409PubMedGoogle Scholar
  77. Watts GS, Pieper RO, Costello JF et al (1997) Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene. Mol Cell Biol 17:5612–5619PubMedGoogle Scholar
  78. Wedge SR, Porteous JK, May BL, Newlands ES (1996a) Potentiation of temozolomide and BCNU cytotoxicity by O(6)-benzylguanine: a comparative study in vitro. Br J Cancer 73:482–490PubMedGoogle Scholar
  79. Wedge SR, Porteous JK, Newlands ES (1996b) 3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity. Br J Cancer 74:1030–1036PubMedGoogle Scholar
  80. Wedge SR, Porteous JK, Glaser MG et al (1997) In vitro evaluation of temozolomide combined with X-irradiation. Anticancer Drugs 8:92–97PubMedGoogle Scholar
  81. Wick W, Wick A, Schulz JB et al (2002) Prevention of irradiation-induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase. Cancer Res 62:1915–1919PubMedGoogle Scholar
  82. Woodburn KW (2001) Intracellular localization of the radiation enhancer motexafin gadolinium using interferometric Fourier fluorescence microscopy. J Pharmacol Exp Ther 297:888–894PubMedGoogle Scholar
  83. Xu S, Zakian K, Thaler H et al (2001) Effects of motexafin gadolinium on tumor metabolism and radiation sensitivity. Int J Radiat Oncol Biol Phys 49:1381–1390PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • Minesh P. Mehta
    • 1
  1. 1.Department of Human OncologyUniversity of Wisconsin Hospital Medical SchoolMadisonUSA

Personalised recommendations