Key Publications - Amplimexon®

  1. Micksche M. Kokoschka EM, Sagaster P, Bicker U: Clinical and immunological investigations of a new immune stimulating drug DM 06.002 (Imexon). In: H Rainer, H Borberg, JM Mishler, Schafer U (eds) Immunotherapy of Malignant Diseases, F.K. Schattauer, Verlag, Stuttgart-New York, 1978, pp. 177-181.
  2. Micksche M, Kokoschka EM, Sagaster P, Bicker U: Phase I study for a new immunostimulating drug, BM 06.002, in man. In: MA Chirigos (ed) Immune Modulation and Control of Neoplasia by Adjuvant Therapy, Raven Press, New York, 1978, pp. 403-413.
  3. Micksche M, Colot M, Uchida A, Kokoschka EM, Lugar TA, Dittrich C, Moser K, Rainer H, Lanzhofer R, Kolb R, Jakesz R, Schemper M, Kakron O, Zwick H, Scheiner A, Flicker H, Sagaster P. Immunomodulation in cancer patients by synthetic biological response modifiers. Cancer Treat Symp 1:27-35, 1985.
  4. Hersh EM, Gschwind CR, Taylor CW, Dorr RT, Taetle R, Salmon SE: Antiproliferative and antitumor activity of the 2-cyanoaziridine compound Imexon on tumor cell lines and fresh tumor cells in vitro. J Natl Cancer Inst 84:1238-1244, 1992.
  5. Funk CY, Eisman J, Hersh EM: Treatment of the murine, retrovirus-induced lymphoproliferative immunodeficiency disease (LP-BM5) in C57BL/10 mice with the immunomodulator Imexon. AIDS Res Human Retroviruses 8:633-638, 1992.
  6. Hersh EM, Grogan TM, Funk CY, Taylor CW: Suppression of human lymphoma development in the severe combined immune-deficient mouse by Imexon therapy. J Immunotherapy 13:77-83, 1993.
  7. Salmon SE, Hersh EM: Sensitivity of multiple myeloma to Imexon in the human tumor cloning assay. J Natl Cancer Inst 86(3):228-230, 1994.
  8. Dorr RT, Liddil JD, Klein MK, Hersh EM: Preclinical pharmacokinetics and antitumor activity of Imexon. Invest New Drugs 13:113-116, 1995.
  9. Sagaster P, Kokoschka EM, Kokron O, Micksche M: Antitumor activity of Imexon. J. Natl Cancer Inst 87(12):935-936, 1995.
  10. Dvorakova K, Payne CM, Tome M, etal. Induction of oxidative stress and apoptosis in myeloma cells by Imexon, Biochem Pharmacol 60(6):749-758, 2000.
  11. Dvorakova K, Waltmire CN, Payne CM, et al. Induction of mitochondrial changes in myeloma cells by Imexon. Blood, 97:3544-3551, 2001.
  12. Dvorakova K, Payne CM, Tome ME, et al. Molecular and cellular characterization of Imexon-resistant RPMI8226/I myeloma cells. Molecular Cancer Therapeutics, 1:185-195, 2002.
  13. Dvorakova K, Payne CM, Landowski TH, Tome ME, Halperin DS, Dorr RT. Imexon activates an intrinsic apoptosis pathway in RPM18226 myeloma cells. Anticancer Drugs. 13:1-13, 2002.
  14. Jagadish B, Iyengar BS, Sólyom AM, Remers WA, Dorr RT, Yu JS, Gupta S, Mash EA.  Synthesis of [14C]-imexon. J Label Compd Radiopharm. 48:165-170, 2005.
  15. Dorr RT, Raymond MA, Landowski TH, Roman NO, Fukushima S.  Induction of apoptosis and cell cycle arrest by imexon in human pancreatic cancer cell lines.  Intl J of Gastrointest Cancer. 36(1): 15-28, 2005.
  16. Lyengar BS, Dorr RT, Remers WA. Chemical basis for the biological activity of imexon and related cyanoaziridines. J Med Chem. 47:218-223, 2004.
  17. Samulitis B, Landowski T, Dorr RT.  Correlates of imexon sensitivity in human multiple myeloma cell lines. Leuk Lymphoma. 47(1):97-109, 2006

  18. Pourpak A, Meyers RO, Samulitis BK, Chow H-H, Kelper CY, Raymond MA, Hersh E, Dorr RT. Preclinical antitumor activity, pharmacokinetics and pharmacodynamics of imexon in mice. Anticancer Drugs. 17(10):1179-84, 2006.

    19.

  19.  Scott J, Dorr RT, Samulitis B, Landowski T.  Imexon-based combination chemotherapy in A375 human melanoma and RPMI 8226 human myeloma cell lines. Cancer Chemother Pharmacol. 59(6);749-57, 2007.

  20. Baker AF, Landowski T, Dorr R, Tate WR, Gard JMC, Tavenner BE, Dragovich T, Coon A, Powis G.  The antitumor agent imexon activates antioxidant gene expression: Evidence for an oxidative stress response. Clin Cancer Res. 13(11):3388-94, 2007.

  21. Dragovich T, Gordon M, Mendelson D, Wong L, Modiano M, Chow S, Samulitis B, O’Day S, Grenier K, Hersh E, Dorr RT.  Phase I trial of imexon in patients with advanced malignancy. J Clin Oncol. 25(13):1779-84, 2007.

  22. Samulitis BK, Landowski T, Dorr RT, Inhibition of protein synthesis by imexon reduces HIF-1x expression in normoxic and hypoxic pancreatic cancer cells, Invest new drug (epub ahead); 2008

 

 

Key Abstracts - Amplimexon®

  1. Dorr RT, Liddil JD, Dalton WS, Galler L, Hersh EM.  The cyanoaziridine imexon (I) produces protein-linked DNA single strand breaks (SSB) possibly by topoisomerase I inhibition  Proc Am Assoc Cancer Res. Abstract #1951, 34:328, 1993.
  2. Hersh EM, Edwards WR, Taylor CW, Dorr RT, Taetle R, Dalton WS, Salmon SE.  In vitro and in vivo antitumor activity of the cyanoaziridine compound imexon.  Proc Am Assoc Cancer Res. Abstract #2229, 34:374, 1993.
  3. Hersh EM, Dorr RT, Grogan TM, Salmon SE.  Imexon:  An active, non-myelosuppressive anticancer agent with relative specificity for B-cell tumors.  NCI/EORTC Symposium, Abstract #096, Ann Oncol 5(Suppl 5):92, 1994.
  4. Hersh EM, Dorr RT, Curtis RA, Prince JE.  Anti-tumor effects of the 2-cyanoaziridine imexon (IM) combined with myelosuppressive and non-myelosuppressive anti-cancer agents. Proc Am Assoc Cancer Res. 36:294, 1995.
  5. Dvorakova K, Iyengar BS, Remers WA, Dorr RT.  Imexon cytotoxicity in 8226 human myeloma cells is associated with decreased levels of cellular thiols, decreased glutathione reductase activity and no DNA alkylation.  Proc Am Assoc Cancer Res. Abstract #469, 39:469, 1998.
  6. Dvorakova K, Remers W, Iyengar B, Dorr R.  Mechanism of imexon action in human myeloma cells.  Proc Am Assoc Cancer Res. 40:2, 1999.
  7. Dorr R, Dvorakova K. Iyengar B, Remers W.  Novel Antitumor 2-cyanoaziridines bind thiols, perturb mitochondrial membrane potential and induce apoptosis in solid tumors.  Proc AACR, NCI, and EORTC Meeting: Molecular Targets and Cancer Therapeutics: Discovery, Development, and Clinical Validation, Washington D.C, 1999, p.38.
  8. Dvorakova K, Dorr RT.  Imexon, new anticancer drug, induces mitochrondrial swelling, release of cytochrome C and loss of mitochondrial membrane potential (MMP) in 8226 myeloma cells.  Proc Am Assoc Cancer Res. Abstract # 2705, 41:425, 2000
  9. Dvorakova K, Dorr RT.  Imexon, new anticancer drug, induces oxidative stress, formation of megamitochondria and loss of mitochondrial membrane potential (MMP). Mitochondrial Damage Abstract, Santa Fe, NM, 2/2000.
  10. Dvorakova K, Waltmire CN, Payne CM, Tome ME, Briehl MM, Dorr RT.  Induction of apoptosis and mitochondrial alteration in malignant cells by imexon. Keystone Symposium, January 2001.
  11. Dvorakova K, Waltmire CN, Payne CM, Tome ME, Dorr RT.  Induction of apoptotic changes in malignant cell lines by new anticancer drug imexon.  Proc Am Assoc Cancer Res. Abstract # 3463, 42:644, 2001.
  12. Dvorakova K, Waltmire CN, Payne CM, Vasquez MA, Tome ME, Briehl MM, Dorr RT.  Characterization of RPMI 8226 cell line resistant to the anticancer drug imexon (IMX).  Proc Am Assoc Cancer Res. Abstract #3464, 42:644, 2001.
  13. Dvorakova K, Payne CM, Tome MM, Halperin DS, Dorr RT. Imexon activates an intrinsic apoptosis pathway in RPM18336 myeloma cells and induces the translocation of BCL-XL to the mitochondria. Proc Am Assoc Cancer Res.  Abstract # 2029, pg. 408, 2002.
  14. Dorr RT, Dvorakova K, Powis G, Samulitis B.  Correlates of imexon (MIX) sensitivity in multiple myeloma (MM) cell lines.  Proc Am Assoc Cancer Res Abstract #5593, page 1292, 2003.
  15. Dorr RT, Roman N, Raymond MA, Pourpak A, Landowski T.  Imexon has antitumor activity against human pancreatic cancer.  Proc Am Assoc Cancer Res. Abstract # 2064, pg. 475, 2004.
  16. Dorr RT, Dragovich T, Hersh E, Patrick K. Phase I clinical trial of imexon: a mitochondrial thiol oxidant. 40th Annual ASCO Mtg, Abstract #3181, pg. 239s, 2004.
  17. Dorr RT, Roman N, Raymond MR, Landowski T, Hersh E.  Imexon induces apoptosis in human pancreatic cancer cells by alteration of cellular redox status.  Pancreatic Cancer 2004: Advances and Challenges, San Francisco, CA, June 2004.
  18. Fukushima S, Landowski TH, Raymond MA, Roman N, Dorr RT.  Imexon induces cell cycle arrest and apoptosis against human pancreatic cancer cell line (MiaPaCa-2) in vitro.  AACR Meeting Cell Cycle and Cancer: Pathways and Therapies, Abstract #1509, December 1-5, 2004.
  19. Roman NO, Fukushima S, Raymond MA, Landowski T, Dorr RT.  Imexon and gemcitabine are synergistic against human pancreatic ancer cells in vitro and in vivo.  Proc Am Assoc Cancer Res. Abstract #5884, Vol 46:1385, 2005. 
  20. Dragovich T, Mendelson D, Gordon M, Long K, Downhour M, Dorr R, Hersh E.  Phase I Trial of imexon (IMX) in patients (pts) with advanced solid tumors. ASCO Annual Mtg 2005. Abstract #3153,  Vol 23:229s, 2005
  21. Dragovich T, Mendeslon D, Gordon M, Wong L, Dorr R, Chow S, Grenier K, Hersh E.  Phase I trial of AmplimexonÔ (imexon, inj.) in patients with advanced solid tumors.  2005 EORTC-NIH-AACR Meeting, Philadelphia, PA.
  22. Samulitis BK, Landowski TH, Dorr RT. Imexon, a novel inhibitor of hypoxia-inducing factor (HIF)-1a in human pancreatic cancer cells. Proc Am Assoc Cancer Res. Abstract # 3819, Vol 47:898, 2006.
  23.  S. L. Moulder, N. Dhillon, D. S. Hong, C. S. Ng, L. H. Camacho, E. M. Hersh, K. A. Grenier, M. L. Boytim, R. T. Dorr, R. Kurzrock. A phase I study of imexon in combination with docetaxel (DOC) for the treatment of patients with breast, lung and prostate cancer. J Clin Oncol. Abstract # 3589, 26:175s, 2008.
  24. S. J. Cohen, M. M. Zalupski, M. R. Modiano, P. R. Conkling, Y. Z. Patt, P. Davis, R. T. Dorr, M. L. Boytim, E. M. Hersh. A phase I study of imexon inj plus gemcitabine as first-line therapy for advanced pancreatic cancer with preclinical mechanistic study of dose limiting toxicity. J Clin Oncol. Abstract # 4619, 26:242s, 2008.
  25. W. E. Samlowski, J. S. Weber, R. Gonzalez, A. Ribas, S. J. O'Day, J. J. Stephenson, T. Sato, R. T. Dorr, K. A. Grenier, E. M. Hersh. Phase I/II study of imexon (AMP) plus dacarbazine (DTIC) in patients (Pts) with metastatic malignant melanoma. J Clin Oncol 26. Abstract # 9066, 26:498s, 2008.

  26. Weber J, Samlowski W, Stephenson J, Ribas A, O’Day S, Gonzalez R, Dorr R, Grenier K, Hersh A.  Phase I/II trial of Amplimexon (AMP) plus dacarbazine (DTIC) in patients with stage III or IV malignant melanoma.  Melanoma Symposium, Amsterdam, Netherlands, September 2006.

    27.

  27. Dragovich T, Mendelson D, Modiano M, Gordon M, Grenier K, Dorr R, Hersh E.  Phase I study of AmplimexonÔ (Imexon, inj.) in patients with advanced solid tumors and lymphomas: final report.  EORTC-NIC-AACR, Intl Conference, “Molecular Targets & Cancer Therapeutic”, 2006.

  28. Thompson MA, Pham L, Tamayo A, Yoshimura L, Hersh EM, Dorr RT, Ford RT. Imexon is an active novel agent in mantle cell lymphoma. Int’l Soc Study Xenobiotic, Drug Metabolism Reviews, 38(2):97, Abstr # 153, 2006.

  29. Dragovich T, Mendelson D, Modiano M, Gordon M, Greiner K, Dorr R, Hersh E. Phase I study of Amplimexon™ (Imexon, inj.) in patients with advanced solid tumors and lymphomas: Final report.  18th EORTC-NCI-AACR Symposium “Molecular Targets and Cancer Therapies”, Prague, Czech Republic, Nov 7-8, 2006.

  30. Thompson MA, Pham LV, Yoshimura L, Powis G, Weinshilboum RM, Baker AF, Hersh EM, Dorr RT, Ford Jr, RJ. Redox proteins GST A1, M1, O1, O2, P1, and Prx-3 and Trx-1 association with in vitro imexon sensitivity in multiple myeloma cell lines.  Blood 108:5077, November 2006.

  31. Dhillon N, Moulder S, Hong DS, Ng C, Camacho LH, Hersh E, Grenier K, Dorr R, Kurzrock R, Phase I trial of imexon and docetaxel in patients with previously-treated stage IV non-small cell lung cancer, metastatic breast cancer or hormone-refractory prostate cancer.  AACR Clinical Abstracts, AACR 98th Annual Meeting, Abstr #LB-351, LB Page 89, Suppl, 2007.

  32. Samulitis B, Dorr RT, Schwartz B, Chow S.  Interaction between imexon (IMX) and dacarbazxine (DTIC) in malignant melanoma (MM) cells in vitro and in vivo.  AACR 98th Annual Meeting, Abstr #4048, 49:962, 2008

  33. Moulder SL, Dhillon N, Hong DS, Ng CS, Camacho LH, Hersh EM, Grenier KA, Boytim ML, Dorr RT, Kurzrock R. A phase I study of imexon in combination with docetaxel (DOC) for the treatment of patients with breast, lung and prostate cancer. (AMP-010)  ASCO Annual Mtg, Abstr #3589, 26:175s, 2008.

  34. Cohen SJ, Zalupski MM, Modiano MR, Conkling PR, Patt YZ, Davis P, Dorr RT, Boytim ML, Hersh EM.  A phase I study of imexon inj. plus gemcitabine as firstline therapy for advanced pancreatic cancer with preclinical mechanistic study of dose limiting toxicity. (AMP-004) ASCO Annual Mtg, Abstr # 4619 26:242s, 2008.

  35. Samlowski WE, Weber JS, Gonzalez R, Ribas A, O’Day SJ, Stephenson JJ, Sato T, Dorr RT, Grenier KA, Hersh EM. Phase I/II study of imexon (AMP) plus dacarbazine (DTIC) in patients (Pts) with metastatic malignant melanoma.  (AMP-005)  ASCO Annual Mtg, Abstr #9066, 26:498s, 2008.

 

Key Publications - Amplizone®

  1. Lyengar BS, Dorr RT, Alberts DS, Hersh EM, Salmon SE, Remers WA. Novel antitumor 2-cyanoaziridine-1-carboxamides. J Med Chem. 42:510-514, 1990.
  2. Sami SM, Dorr RT, Alberts DS, Remers WA.  2-Substituted-1,2-dihydro-3H-dibenz(de,h)isoquinoline-1,3-diones.  A new class of antitumor agents.  J Med Chem. 36:765-770, 1993.
  3. Sami SM, Dorr RT, Sólyom AM, Alberts DS, Remers WA. Amino substituted 2-[2’-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones.  Synthesis, antitumor activity, and quantitative structure-activity relationship.  J Med Chem. 38:983-993, 1995.
  4. Sami SM, Dorr RT, Sólyom AM, Alberts DS, Iyengar BS, Remers WA. 6- and 7-substituted 2-[2’-(dimethylamino)ethyl]- 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones: Synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationship. J Med Chem. 39(8):1609-1618, 1996.
  5. Remers WA, Alberts DS, Bear S, Dorr RT, Mayr CA, Sami SM, Sólyom AM.  A new class of antitumor agents:  2-Substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. Curr Topics Med Chem. 2:45-61, 1997.
  6. Lyengar BS, Dorr RT, Alberts DS, Sólyom AM, Krutzsch M, Remers WA.  1,4-disubstituted anthracene antitumor agents.  J Med Chem. 40(23):3734-3738, 1997.
  7. Mayr CA, Sami SM, Dorr RT.  In vitro cytotoxicity and DNA damage production in Chinese hamster ovary cells and topoisomerase Il inhibition by 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones with substitutions at the 6 and 7 positions (azonafides).  Anti-Cancer Drugs. 8:245-256, 1997.
  8. Mayr CA, Sami SM, Remers WA, Dorr RT.  Identification and characterization of in vitro metabolites of 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-dione (azonafide).  Drug Metab Dispos. 26(2):105-109, 1998.
  9. Mayr CA, Sami SM, Remers WA, Dorr RT.  Intracellular localization of 6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones (azonafides) is not the limiting factor for their cytotoxicity:  An in vitro confocal microscopy study.  Anti-Cancer Drugs. 10:163-170, 1999.
  10. Lyengar BS, Dorr RT, Alberts DS, Hersh EM, Salmon SE, Remers WA.  Novel antitumor 2-cyanoaziridine-1-carboxamides.  J Med Chem. 42:510-514, 1999.
  11. Sami SM, Dorr RT, Alberts DS, Sólyom AM, Remers WA. Analogues of amonafide and azonafide with novel ring systems. J Med Chem. 43:3067-3073, 2000.
  12. Pourpak A, Landowski TH, Dorr RT. Ethonafide-induced cytotoxicity is mediate by topoisomerase II inhibition in prostate cancer cells.  J Pharma Exper Therap. 321(3):1109-17, 2007
    13.

  13. Piao WH, Wong R, Bai XF, Huang J, Campagnolo DI, Dorr RT, Vollmer TL, Shi FD.  Therapeutic effect of anthracene-based anticancer agent ethonafide in an animal model of multiple sclerosis.  J Immunol 179:7415-23, 2007.

 

Key Abstracts - Amplizone®

  1. Dorr RT, Alberts DS, Sami SM, Remers WA.  Consistent cytotoxic activity in multidrug resistant tumors for azonafide, a new anthracene analog of amonafide.  Proc Am Assoc Cancer Res. Abstract #2424, 32:408, l991.
  2. Dorr RT, Remers WA, Sami S, Alberts DS.  Structure-activity relationships for anthracene derivatives of amonafide termed azonafides.  Proc Am Assoc Cancer Res. Abstract #3129, 33:523, 1992.
  3. Dorr RT, Sami S, Remers WA, Alberts DS, Salmon SE, Hersh EM.  The azonafide series of anthracenes with activity in multidrug resistant (MDR) tumors.  NCI/EORTC Symposium, Ann Oncol. Abstract #335, 5(Suppl 5):156, 1994.
  4. Dorr RT, Remers WA, Alberts DS, Salmon SE, Hersh EM.  Activity of a substituted anthracene, AMP-53, in sensitive and multidrug resistant tumors in vitro and in vivo.  Proc Am Assoc Cancer Res. Abstract #2166, 35:364, 1994.
  5. Remers WA, Dorr RT, Sami SM, Solyom AS, Alberts DS:  Quantitative structure-activity relationships of azonafide analogues. Proc Am Assoc Cancer Res. Abstract #2009, 35:337, 1994.
  6. Mayr CA, Remers WA, Dorr RT.  The mechanism of action of a group of anthracene containing analogs of amonafide, the azonafides.  Proc Am Assoc Cancer Res. Abstract #2442, 37:358, 1996.
  7. Mayr, C, Sami S, Dorr R. Microsomal metabolism of azonafide results in decreased cytotoxic and topoisomerase II (TOPO II) inhibitory potencies. Proc Am Assoc Cancer Res. Abstract #1525, 38:226, 1997.

  8. Pourpak A, Landowski TH, Dorr RT. Ethonafide-induced cytotoxicity is mediated by topoisomerase II inhibition in human prostate cancer cells. AACR 97th Annual Meeting, Abstr # 5537,  47:1302, 2006.