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RH1

RH1 is a new bioreductive agent that is an excellent substrate for the two-electron reducing enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1). RH1 may be an effective NQO1-directed antitumor agent for treatment of cancer cells having elevated NQO1 activity. As some studies have indicated that RH1 may also be a substrate for the one-electron reducing enzyme, NADPH cytochrome P 450 reductase (P 450 Red), P 450 Red may contribute to the activation of RH1 where NQO1 activities are low and P 450 Red activities are high. The mean P 450 Red activity in the human tumor cell line panel used by NCI for evaluation of new anticancer agents is 14.8 nmol min-1 mg prot-1, while the mean NQO1 activity in these cell lines is 199.5 nmol min-1 mg prot-1. see:  Begleiter, Asher; Leith, Marsha K.; Patel, Daywin; Hasinoff, Brian B. Cancer Chemotherapy and Pharmacology (2007), 60(5), 713-723.

Current developer:    Allos Therapeutics, Inc

1. Hussein, D.; Holt, S. V.; Brookes, K. E.; Klymenko, T.; Adamski, J. K.; Hogg, A.; Estlin, E. J.; Ward, T.; Dive, C.; Makin, G. W. J. Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours. British Journal of Cancer (2009), 101(1), 55-63. CODEN: BJCAAI ISSN:0007-0920. AN 2009:806387

2. Makin, Guy W. J. Dt-diaphorase-active agents for treatment of pediatric tumors. PCT Int. Appl. (2009), 29pp. CODEN: PIXXD2 WO 2009046127 A1 20090409 CAN 150:390199 AN 2009:425797

3. Begleiter, Asher; Leith, Marsha K.; Patel, Daywin; Hasinoff, Brian B. Role of NADPH cytochrome P450 reductase in activation of RH1. Cancer Chemotherapy and Pharmacology (2007), 60(5), 713-723. CODEN: CCPHDZ ISSN:0344-5704. CAN 148:45226 AN 2007:890833

4. Alcain, Francisco J.; Villalba, Jose M. NQO1-directed antitumour quinones. Expert Opinion on Therapeutic Patents (2007), 17(6), 649-665. CODEN: EOTPEG ISSN:1354-3776. CAN 147:132270 AN 2007:711951

5. Nemeikaite-Ceniene, Ausra; Dringeliene, Aldona; Sarlauskas, Jonas; Cenas, Narimantas. Role of NAD(P)H: quinone oxidoreductase (NQO1) in apoptosis induction by aziridinylbenzoquinones RH1 and MeDZQ. Acta Biochimica Polonica (2005), 52(4), 937-941. CODEN: ABPLAF ISSN:0001-527X. CAN 145:474 AN 2006:235534

6. Ward, Timothy H.; Ranson, Malcolm. Diaziridinyl benzoquinone compounds and compositions for treatment of cancer. PCT Int. Appl. (2005), 53 pp. CODEN: PIXXD2 WO 2005107743 A1 20051117 CAN 143:466217 AN 2005:1220107

7. Dehn, Donna L.; Inayat-Hussain, Salmaan H.; Ross, David. RH1 induces cellular damage in an NAD(P)H:Quinone oxidoreductase 1-dependent manner: Relationship between DNA cross-linking, cell cycle perturbations, and apoptosis. Journal of Pharmacology and Experimental Therapeutics (2005), 313(2), 771-779. CODEN: JPETAB ISSN:0022-3565. CAN 143:641 AN 2005:413534

8. Ward, Timothy H.; Danson, Sarah; McGown, Alan T.; Ranson, Malcolm; Coe, Nic A.; Jayson, Gordon C.; Cummings, Jeff; Hargreaves, Robert H. J.; Butler, John. Preclinical evaluation of the phrmacodynamic poperties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone. Clinical Cancer Research (2005), 11(7), 2695-2701. CODEN: CCREF4 ISSN:1078-0432. CAN 143:145910 AN 2005:296122

9. Tudor, Gabriela; Alley, Mike; Nelson, Christopher M.; Huang, Ruili; Covell, David G.; Gutierrez, Peter; Sausville, Edward A. Cytotoxicity of RH1. NAD(P)H:quinone acceptor oxidoreductase (NQO1)-independent oxidative stress and apoptosis induction. Anti-Cancer Drugs (2005), 16(4), 381-391. CODEN: ANTDEV ISSN:0959-4973. CAN 142:403607 AN 2005:178897

10. Ross, David. Quinone Reductases Multitasking in the Metabolic World. Drug Metabolism Reviews (2004), 36(3-4), 639-654. CODEN: DMTRAR ISSN:0360-2532. CAN 142:189907 AN 2004:909174

11. Danson, S.; Ward, T. H.; Butler, J.; Ranson, M. DT-diaphorase: a target for new anticancer drugs. Cancer Treatment Reviews (2004), 30(5), 437-449. CODEN: CTREDJ ISSN:0305-7372. CAN 142:106205 AN 2004:558194

12. Dehn, Donna Labar. Studies on the mechanism of toxicity of the novel NQO1-directed antitumor agent, RH1. (2003), 231 pp. CAN 141:343014 AN 2004:388580

13. Dehn, Donna L.; Winski, Shannon L.; Ross, David. Development of a new isogenic cell-Xenograft system for evaluation of NAD(P)H:quinone oxidoreductase-directed antitumor quinones: evaluation of the activity of RH1. Clinical Cancer Research (2004), 10(9), 3147-3155.

14. Kim, J. Y.; Patterson, A. V.; Stratford, I. J.; Hendry, J. H. The importance of DT-diaphorase and hypoxia in the cytotoxicity of RH1 in human breast and non-small cell lung cancer cell lines. Anti-Cancer Drugs (2004), 15(1), 71-77.

15. Begleiter, Asher; Fourie, Jeanne. Induction of NQO1 in cancer cells. Methods in Enzymology (2004), 382(Quinones and Quinone Enzymes, Part B), 320-351.

16. Kim, Joo-Young; West, C. M. L.; Valentine, H.; Ward, T. H.; Patterson, A. V.; Stratford, I. J.; Roberts, S. A.; Hendry, J. H. Cytotoxicity of the bioreductive agent RH1 and its lack of interaction with radiation. Radiotherapy and Oncology (2004), 70(3), 311-317.

17. Kim, Joo-Young; Kim, Chul-Hwan; Stratford, Ian J.; Patterson, Adam V.; Hendry, Jolyon H. The bioreductive agent RH1 and  -irradiation both cause G2/M cell cycle phase arrest and polyploidy in a p53-mutated human breast cancer cell line. International Journal of Radiation Oncology, Biology, Physics (2004), 58(2), 376-385.

18. Cummings, Jeffrey; Ritchie, Alison; Butler, John; Ward, Timothy H.; Langdon, Simon. Activity profile of the novel aziridinylbenzoquinones MeDZQ and RH1 in human tumour xenografts. Anticancer Research (2003), 23(5A), 3979-3983.

19. Nemeikaite-Ceniene, Ausra; Sarlauskas, Jonas; Anusevicius, Zilvinas; Nivinskas, Henrikas; Cenas, Narimantas. Cytotoxicity of RH1 and related aziridinylbenzoquinones: involvement of activation by NAD(P)H:quinone oxidoreductase (NQO1) and oxidative stress. Archives of Biochemistry and Biophysics (2003), 416(1), 110-118.

20. Elliott, M. A.; Ford, S. J.; Walker, A. A.; Hargreaves, R. H. J.; Halbert, G. W. Development of a lyophilised RH1 formulation: a novel DT diaphorase activated alkylating agent. Journal of Pharmacy and Pharmacology (2002), 54(4), 487-492.

21. Faig, M.; Bianchet, M. A.; Winski, S.; Hargreaves, R.; Moody, C. J.; Hudnott, A. R.; Ross, D.; Amzel, L. M. Structure-Based Development of Anticancer Drugs. Complexes of NAD(P)H:Quinone Oxidoreductase 1 with Chemotherapeutic Quinones. Structure (Cambridge, MA, United States) (2001), 9(8), 659-667.

22. Winski, S. L.; Swann, E.; Hargreaves, R. H. J.; Dehn, D. L.; Butler, J.; Moody, C. J.; Ross, D. Relationship between NAD(P)H:quinone oxidoreductase 1 (NQO1) levels in a series of stably transfected cell lines and susceptibility to antitumor quinones. Biochemical Pharmacology (2001), 61(12), 1509-1516.

23. Sharp, Swee Y.; Kelland, Lloyd R.; Valenti, Melanie R.; Brunton, Lisa A.; Hobbs, Steve; Workman, Paul. Establishment of an isogenic human colon tumor model for NQO1 gene expression: application to investigate the role of DT-diaphorase in bioreductive drug activation in vitro and in vivo. Molecular Pharmacology (2000), 58(5), 1146-1155.

24. Xing, Chengguo; Skibo, Edward B. Sigmatropic reactions of the aziridinyl semiquinone species. why aziridinyl benzoquinones are metabolically more stable than aziridinyl indoloquinones. Biochemistry (2000), 39(35), 10770-10780.

25. Loadman, P. M.; Phillips, R. M.; Lim, L. E.; Bibby, M. C. Pharmacological properties of a new aziridinylbenzoquinone, RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), in mice. Biochemical Pharmacology (2000), 59(7), 831-837.

26. Winski, Shannon L.; Hargreaves, Robert H. J.; Butler, John; Ross, David. A new screening system for NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor quinones: identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent. Clinical Cancer Research (1998), 4(12), 3083-3088.