MedKoo product information:

RH1

Description of 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). In phase trials, RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 μg/m(2)/day is the dose recommended for phase II trials. The biomarkers of DNA cross linking, DTD activity and NQO1 status have been validated and clinically developed.

Current developer:    Allos Therapeutics, Inc  

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.

1: Danson SJ, Johnson P, Ward TH, Dawson M, Denneny O, Dickinson G, Aarons L, Watson A, Jowle D, Cummings J, Robson L, Halbert G, Dive C, Ranson M. Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1. Ann Oncol. 2011 Jul;22(7):1653-60. doi: 10.1093/annonc/mdq638. Epub 2011 Mar 4. PubMed PMID: 21378203.

2: Park MT, Song MJ, Oh ET, Lee H, Choi BH, Jeong SY, Choi EK, Park HJ. The anti-tumour compound, RH1, causes mitochondria-mediated apoptosis by activating c-Jun N-terminal kinase. Br J Pharmacol. 2011 Jun;163(3):567-85. doi: 10.1111/j.1476-5381.2011.01233.x. PubMed PMID: 21250978; PubMed Central PMCID: PMC3101619.

3: Hussein D, Holt SV, Brookes KE, Klymenko T, Adamski JK, Hogg A, Estlin EJ, Ward T, Dive C, Makin GW. Preclinical efficacy of the bioreductive alkylating agent RH1 against paediatric tumours. Br J Cancer. 2009 Jul 7;101(1):55-63. doi: 10.1038/sj.bjc.6605100. Epub 2009 Jun 2. PubMed PMID: 19491903; PubMed Central PMCID: PMC2713707.

4: Begleiter A, Leith MK, Patel D, Hasinoff BB. Role of NADPH cytochrome P450 reductase in activation of RH1. Cancer Chemother Pharmacol. 2007 Oct;60(5):713-23. Epub 2007 Jan 26. PubMed PMID: 17256129.

5: Hasinoff BB, Begleiter A. The reductive activation of the antitumor drug RH1 to its semiquinone free radical by NADPH cytochrome P450 reductase and by HCT116 human colon cancer cells. Free Radic Res. 2006 Sep;40(9):974-8. PubMed PMID: 17015278.

6: Digby T, Leith MK, Thliveris JA, Begleiter A. Effect of NQO1 induction on the antitumor activity of RH1 in human tumors in vitro and in vivo. Cancer Chemother Pharmacol. 2005 Sep;56(3):307-16. Epub 2005 May 5. PubMed PMID: 15877230.

7: Kim JY, West CM, Valentine H, Ward TH, Patterson AV, Stratford IJ, Roberts SA, Hendry JH. Cytotoxicity of the bioreductive agent RH1 and its lack of interaction with radiation. Radiother Oncol. 2004 Mar;70(3):311-7. PubMed PMID: 15064018.

8: Kim JY, Kim CH, Stratford IJ, Patterson AV, Hendry JH. The bioreductive agent RH1 and gamma-irradiation both cause G2/M cell cycle phase arrest and polyploidy in a p53-mutated human breast cancer cell line. Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):376-85. PubMed PMID: 14751506.

9: Nemeikaite-Ceniene A, Sarlauskas J, Anusevicius Z, Nivinskas H, Cenas N. Cytotoxicity of RH1 and related aziridinylbenzoquinones: involvement of activation by NAD(P)H:quinone oxidoreductase (NQO1) and oxidative stress. Arch Biochem Biophys. 2003 Aug 1;416(1):110-8. PubMed PMID: 12859987.