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Motexafin gadolinium

Description of Motexafin gadolinium: motexafin gadolinium is a synthetic metallotexaphyrin with radiosensitizing and chemosensitizing properties. Motexafin gadolinium accumulates in tumor cells preferentially due to their increased rates of metabolism, generating reactive oxygen species (ROS) intracellularly and lowering the tumor cell apoptotic threshold to ionizing radiation and chemotherapy. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    Pharmacyclics (Originator), National Cancer Institute (Codevelopment).

Phase I trials of  Motexafin gadolinium (MTG): Fifteen patients received 37 cycles of treatment, for a median of 2 cycles per patient (range 0-6 cycles). Three patients (20%) completed 6 cycles of therapy. The MTD was identified as MGd, 2 mg/kg/day and doxorubicin, 30 mg/m². Dose limiting toxicities included grade 3 hypertension, pneumonia, bacteremia, and elevated GGT. Serious adverse events also included pulmonary embolism and urinary tract infection requiring hospitalization. There was no exacerbation of cardiac toxicity. No patients attained a response to treatment. Six patients (54%) had stable disease. The median time to disease progression, or to last assessment, was 49 days (range 8-195 days). CONCLUSIONS:  The combination of MGd and doxorubicin was fairly well tolerated. However, due to emerging preclinical data suggesting that MGd inhibits ribonucleotide reductase, further development of the combination of MGd plus doxorubicin is not recommended. (source: Invest New Drugs. 2011 Apr;29(2):316-22).

 1: McHaffie DR, Chabot P, Dagnault A, Suh JH, Fortin MA, Chang E, Timmerman R, Souhami L, Grecula J, Nabid A, Schultz C, Werner-Wasik M, Gaspar LE, Brachman D, Mody T, Mehta MP. Safety and feasibility of motexafin gadolinium administration with whole brain radiation therapy and stereotactic radiosurgery boost in the treatment of ≤ 6 brain metastases: a multi-institutional phase II trial. J Neurooncol. 2011 Nov;105(2):301-8. Epub 2011 Apr 27. PubMed PMID: 21523486.

2: Berndt C, Kurz T, Bannenberg S, Jacob R, Holmgren A, Brunk UT. Ascorbate and endocytosed Motexafin gadolinium induce lysosomal rupture. Cancer Lett. 2011 Aug 28;307(2):119-23. Epub 2011 Apr 13. PubMed PMID: 21492999.

3: Edelman MJ, Otterson G, Leach J, Malpass T, Salgia R, Jones D, Mody TD, Govindan R. Multicenter phase II trial of Motexafin gadolinium and pemetrexed for second-line treatment in patients with non-small cell lung cancer. J Thorac Oncol. 2011 Apr;6(4):786-9. PubMed PMID: 21289521.

4: Singh AT, Evens AM, Prachand SN, Gordon LI. Motexafin gadolinium enhances p53-Mdm2 interactions, reducing p53 and downstream targets in lymphoma cell lines. Anticancer Res. 2010 Apr;30(4):1131-6. PubMed PMID: 20530418.

5: Traynor AM, Thomas JP, Ramanathan RK, Mody TD, Alberti D, Wilding G, Bailey HH. Phase I trial of motexafin gadolinium and doxorubicin in the treatment of advanced malignancies. Invest New Drugs. 2011 Apr;29(2):316-22. Epub 2009 Dec 9. PubMed PMID: 19997959; PubMed Central PMCID: PMC3038176.

6: Lin TS, Naumovski L, Lecane PS, Lucas MS, Moran ME, Cheney C, Lucas DM, Phan SC, Miller RA, Byrd JC. Effects of motexafin gadolinium in a phase II trial in refractory chronic lymphocytic leukemia. Leuk Lymphoma. 2009 Dec;50(12):1977-82. PubMed PMID: 19860624.

7: Evens AM, Spies WG, Helenowski IB, Patton D, Spies S, Jovanovic BD, Miyata S, Hamilton E, Variakojis D, Chen J, Naumovski L, Rosen ST, Winter JN, Miller RA, Gordon LI. The novel expanded porphyrin, motexafin gadolinium, combined with [90Y]ibritumomab tiuxetan for relapsed/refractory non-Hodgkin's lymphoma: preclinical findings and results of a phase I trial. Clin Cancer Res. 2009 Oct 15;15(20):6462-71. Epub 2009 Oct 13. PubMed PMID: 19825958; PubMed Central PMCID: PMC2763343.

8: Francis D, Richards GM, Forouzannia A, Mehta MP, Khuntia D. Motexafin gadolinium: a novel radiosensitizer for brain tumors. Expert Opin Pharmacother. 2009 Sep;10(13):2171-80. PubMed PMID: 19640206.

9: Kanick SC, Eiseman JL, Parker RS. Pharmacokinetic modeling of motexafin gadolinium disposition in mouse tissues using optical pharmacokinetic system measurements. Photodiagnosis Photodyn Ther. 2008 Dec;5(4):276-84. Epub 2009 Jan 23. PubMed PMID: 19356671.

10: Zahedi Avval F, Berndt C, Pramanik A, Holmgren A. Mechanism of inhibition of ribonucleotide reductase with motexafin gadolinium (MGd). Biochem Biophys Res Commun. 2009 Feb 13;379(3):775-9. Epub 2009 Jan 1. PubMed PMID: 19121624.

11: Mehta MP, Shapiro WR, Phan SC, Gervais R, Carrie C, Chabot P, Patchell RA, Glantz MJ, Recht L, Langer C, Sur RK, Roa WH, Mahe MA, Fortin A, Nieder C, Meyers CA, Smith JA, Miller RA, Renschler MF. Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial. Int J Radiat Oncol Biol Phys. 2009 Mar 15;73(4):1069-76. Epub 2008 Oct 30. PubMed PMID: 18977094.

12: Amato RJ, Jac J, Hernandez-McClain J. Motexafin gadolinium for the treatment of metastatic renal cell carcinoma: phase II study results. Clin Genitourin Cancer. 2008 Sep;6(2):73-8. PubMed PMID: 18824428.

13: Madsen SJ, Mathews MS, Angell-Petersen E, Sun CH, Vo V, Sanchez R, Hirschberg H. Motexafin gadolinium enhances the efficacy of aminolevulinic acid mediated-photodynamic therapy in human glioma spheroids. J Neurooncol. 2009 Jan;91(2):141-9. Epub 2008 Sep 6. PubMed PMID: 18777009.

14: Bradley KA, Pollack IF, Reid JM, Adamson PC, Ames MM, Vezina G, Blaney S, Ivy P, Zhou T, Krailo M, Reaman G, Mehta MP; Children's Oncology Group. Motexafin gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a Children's Oncology Group phase I study. Neuro Oncol. 2008 Oct;10(5):752-8. Epub 2008 Aug 20. PubMed PMID: 18715950; PubMed Central PMCID: PMC2666252.

15: Hirschberg H, Wu GN, Madsen SJ. Evaluation of Motexafin gadolinium (MGd) as a contrast agent for intraoperative MRI. Minim Invasive Neurosurg. 2007 Dec;50(6):318-23. PubMed PMID: 18210352.

16: Brushett C, Qiu B, Atalar E, Yang X. High-resolution MRI of deep-seated atherosclerotic arteries using motexafin gadolinium. J Magn Reson Imaging. 2008 Jan;27(1):246-50. PubMed PMID: 18050320.

17: William WN Jr, Zinner RG, Karp DD, Oh YW, Glisson BS, Phan SC, Stewart DJ. Phase I trial of motexafin gadolinium in combination with docetaxel and cisplatin for the treatment of non-small cell lung cancer. J Thorac Oncol. 2007 Aug;2(8):745-50. PubMed PMID: 17762342.

18: Thomas SR, Khuntia D. Motexafin gadolinium injection for the treatment of brain metastases in patients with non-small cell lung cancer. Int J Nanomedicine. 2007;2(1):79-87. Review. PubMed PMID: 17722515; PubMed Central PMCID: PMC2673824.

19: Kanick SC, Eiseman JL, Joseph E, Guo J, Parker RS. Noninvasive and nondestructive optical spectroscopic measurement of motexafin gadolinium in mouse tissues: comparison to high-performance liquid chromatography. J Photochem Photobiol B. 2007 Sep 25;88(2-3):90-104. Epub 2007 May 24. PubMed PMID: 17604637.

20: Ford JM, Seiferheld W, Alger JR, Wu G, Endicott TJ, Mehta M, Curran W, Phan SC. Results of the phase I dose-escalating study of motexafin gadolinium with standard radiotherapy in patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):831-8. Epub 2007 Jun 8. PubMed PMID: 17560737.

21: Forouzannia A, Richards GM, Khuntia D, Mehta MP. Motexafin gadolinium: a novel radiosensitizer for brain tumors. Expert Rev Anticancer Ther. 2007 Jun;7(6):785-94. Review. PubMed PMID: 17555388.

22: Richards GM, Mehta MP. Motexafin gadolinium in the treatment of brain metastases. Expert Opin Pharmacother. 2007 Feb;8(3):351-9. Review. PubMed PMID: 17266469.

23: Magda D, Miller RA. Motexafin gadolinium: a novel redox active drug for cancer therapy. Semin Cancer Biol. 2006 Dec;16(6):466-76. Epub 2006 Sep 26. Review. PubMed PMID: 17112739.

24: Evans JP, Xu F, Sirisawad M, Miller R, Naumovski L, de Montellano PR. Motexafin gadolinium-induced cell death correlates with heme oxygenase-1 expression and inhibition of P450 reductase-dependent activities. Mol Pharmacol. 2007 Jan;71(1):193-200. Epub 2006 Oct 3. PubMed PMID: 17018578.

25: Ramos J, Sirisawad M, Miller R, Naumovski L. Motexafin gadolinium modulates levels of phosphorylated Akt and synergizes with inhibitors of Akt phosphorylation. Mol Cancer Ther. 2006 May;5(5):1176-82. PubMed PMID: 16731749.

26: Miles DR, Mesfin M, Mody TD, Stiles M, Lee J, Fiene J, Denis B, Boswell GW. Validation and use of three complementary analytical methods (LC-FLS, LC-MS/MS and ICP-MS) to evaluate the pharmacokinetics, biodistribution and stability of motexafin gadolinium in plasma and tissues. Anal Bioanal Chem. 2006 May;385(2):345-56. Epub 2006 Apr 12. PubMed PMID: 16609840.

27: Wu GN, Ford JM, Alger JR. MRI measurement of the uptake and retention of motexafin gadolinium in glioblastoma multiforme and uninvolved normal human brain. J Neurooncol. 2006 Mar;77(1):95-103. Epub 2006 Mar 18. PubMed PMID: 16547607.

28: Boswell GW, Miles DR, Thiemann PA, Mesfin M. Population pharmacokinetics and bioavailability of motexafin gadolinium (Xcytrin) in CD1 mice following intravenous and intraperitoneal injection. Invest New Drugs. 2006 Jul;24(4):281-9. PubMed PMID: 16538526.

29: Hashemy SI, Ungerstedt JS, Zahedi Avval F, Holmgren A. Motexafin gadolinium, a tumor-selective drug targeting thioredoxin reductase and ribonucleotide reductase. J Biol Chem. 2006 Apr 21;281(16):10691-7. Epub 2006 Feb 14. PubMed PMID: 16481328.

30: De Stasio G, Rajesh D, Ford JM, Daniels MJ, Erhardt RJ, Frazer BH, Tyliszczak T, Gilles MK, Conhaim RL, Howard SP, Fowler JF, Estève F, Mehta MP. Motexafin-gadolinium taken up in vitro by at least 90% of glioblastoma cell nuclei. Clin Cancer Res. 2006 Jan 1;12(1):206-13. PubMed PMID: 16397044.

31: Lecane PS, Karaman MW, Sirisawad M, Naumovski L, Miller RA, Hacia JG, Magda D. Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88. PubMed PMID: 16357179.

32: Chen J, Ramos J, Sirisawad M, Miller R, Naumovski L. Motexafin gadolinium induces mitochondrially-mediated caspase-dependent apoptosis. Apoptosis. 2005 Oct;10(5):1131-42. PubMed PMID: 16151646.

33: Ramanathan RK, Fakih M, Mani S, Deutsch M, Perez RP, Ritter MA, Eiseman JL, Ivy SP, Trump DL, Belani CP, Parise RA, Potter DM, Egorin MJ. Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers. Cancer Chemother Pharmacol. 2006 Apr;57(4):465-74. Epub 2005 Aug 25. PubMed PMID: 16133531.

34: Donnelly ET, Liu Y, Paul TK, Rockwell S. 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. 2005 Jul 15;62(4):1176-86. PubMed PMID: 15990023.

35: Evens AM, Balasubramanian L, Gordon LI. Motexafin gadolinium induces oxidative stress and apoptosis in hematologic malignancies. Curr Treat Options Oncol. 2005 Jul;6(4):289-96. Review. PubMed PMID: 15967082.

36: Magda D, Lecane P, Miller RA, Lepp C, Miles D, Mesfin M, Biaglow JE, Ho VV, Chawannakul D, Nagpal S, Karaman MW, Hacia JG. Motexafin gadolinium disrupts zinc metabolism in human cancer cell lines. Cancer Res. 2005 May 1;65(9):3837-45. PubMed PMID: 15867382.

37: Miles DR, Smith JA, Phan SC, Hutcheson SJ, Renschler MF, Ford JM, Boswell GW. Population pharmacokinetics of motexafin gadolinium in adults with brain metastases or glioblastoma multiforme. J Clin Pharmacol. 2005 Mar;45(3):299-312. PubMed PMID: 15703365.

38: Mani C, Upadhyay S, Lacy S, Boswell GW, Miles DR. Reductase-mediated metabolism of motexafin gadolinium (Xcytrin) in rat and human liver subcellular fractions and purified enzyme preparations. J Pharm Sci. 2005 Mar;94(3):559-70. PubMed PMID: 15666291.

39: Evens AM. Motexafin gadolinium: a redox-active tumor selective agent for the treatment of cancer. Curr Opin Oncol. 2004 Nov;16(6):576-80. Review. PubMed PMID: 15627019.

40: Khuntia D, Mehta M. Motexafin gadolinium: a clinical review of a novel radioenhancer for brain tumors. Expert Rev Anticancer Ther. 2004 Dec;4(6):981-9. Review. PubMed PMID: 15606327.

41: Evens AM, Lecane P, Magda D, Prachand S, Singhal S, Nelson J, Miller RA, Gartenhaus RB, Gordon LI. Motexafin gadolinium generates reactive oxygen species and induces apoptosis in sensitive and highly resistant multiple myeloma cells. Blood. 2005 Feb 1;105(3):1265-73. Epub 2004 Sep 23. PubMed PMID: 15388578.

42: Motexafin gadolinium: gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120. Drugs R D. 2004;5(1):52-7. Review. PubMed PMID: 14725495.

43: Meyers CA, Smith JA, Bezjak A, Mehta MP, Liebmann J, Illidge T, Kunkler I, Caudrelier JM, Eisenberg PD, Meerwaldt J, Siemers R, Carrie C, Gaspar LE, Curran W, Phan SC, Miller RA, Renschler MF. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: results of a randomized phase III trial. J Clin Oncol. 2004 Jan 1;22(1):157-65. PubMed PMID: 14701778.

44: Dehnad H, Kal HB, Stam T, Gademan IS, van Moorselaar RJ, van der Sanden BP. Response to motexafin gadolinium and ionizing radiation of experimental rat prostate and lung tumors. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):787-93. PubMed PMID: 14529785.

45: Rodrigus P. Motexafin gadolinium: a possible new radiosensitiser. Expert Opin Investig Drugs. 2003 Jul;12(7):1205-10. Review. PubMed PMID: 12831354.

46: Mehta MP, Rodrigus P, Terhaard CH, Rao A, Suh J, Roa W, Souhami L, Bezjak A, Leibenhaut M, Komaki R, Schultz C, Timmerman R, Curran W, Smith J, Phan SC, Miller RA, Renschler MF. Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol. 2003 Jul 1;21(13):2529-36. PubMed PMID: 12829672.

47: Magda D, Gerasimchuk N, Lecane P, Miller RA, Biaglow JE, Sessler JL. Motexafin gadolinium reacts with ascorbate to produce reactive oxygen species. Chem Commun (Camb). 2002 Nov 21;(22):2730-1. PubMed PMID: 12510321.

48: Mehta MP, Shapiro WR, Glantz MJ, Patchell RA, Weitzner MA, Meyers CA, Schultz CJ, Roa WH, Leibenhaut M, Ford J, Curran W, Phan S, Smith JA, Miller RA, Renschler MF. 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. 2002 Aug 15;20(16):3445-53. PubMed PMID: 12177105.

49: Perez OD, Nolan GP, Magda D, Miller RA, Herzenberg LA, Herzenberg LA. Motexafin gadolinium (Gd-Tex) selectively induces apoptosis in HIV-1 infected CD4+ T helper cells. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2270-4. PubMed PMID: 11854523; PubMed Central PMCID: PMC122354.

50: Magda D, Lepp C, Gerasimchuk N, Lee I, Sessler JL, Lin A, Biaglow JE, Miller RA. Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species. Int J Radiat Oncol Biol Phys. 2001 Nov 15;51(4):1025-36. PubMed PMID: 11704327.

51: Miller RA, Woodburn KW, Fan Q, Lee I, Miles D, Duran G, Sikic B, Magda D. Motexafin gadolinium: a redox active drug that enhances the efficacy of bleomycin and doxorubicin. Clin Cancer Res. 2001 Oct;7(10):3215-21. PubMed PMID: 11595717.

52: Woodburn KW. Intracellular localization of the radiation enhancer motexafin gadolinium using interferometric Fourier fluorescence microscopy. J Pharmacol Exp Ther. 2001 Jun;297(3):888-94. PubMed PMID: 11356908.

53: Xu S, Zakian K, Thaler H, Matei C, Alfieri A, Chen Y, Koutcher JA. Effects of Motexafin gadolinium on tumor metabolism and radiation sensitivity. Int J Radiat Oncol Biol Phys. 2001 Apr 1;49(5):1381-90. PubMed PMID: 11286846.

54: Carde P, Timmerman R, Mehta MP, Koprowski CD, Ford J, Tishler RB, Miles D, Miller RA, Renschler MF. Multicenter phase Ib/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases. J Clin Oncol. 2001 Apr 1;19(7):2074-83. PubMed PMID: 11283141.

55: Parise RA, Miles DR, Egorin MJ. Sensitive high-performance liquid chromatographic assay for motexafin gadolinium and motexafin lutetium in human plasma. J Chromatogr B Biomed Sci Appl. 2000 Dec 1;749(2):145-52. PubMed PMID: 11145051.