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Sivifene

Sivifene gel is the phenylhydrazone 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone formulated as a topical agent with immunomodulating and potential antineoplastic activities. Applied topically as a gel, sivifene may stimulate a local immune response against human papillomavirus (HPV)-induced cervical intraepithelial neoplasia (CIN). Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

According to recent publication (see: http://www.ncbi.nlm.nih.gov/pubmed/11887332), 4,4'-Dihydroxybenzophenone-2,4-ditrophenylhydrazone (A-007) has demonstrated anticancer activities, when administered topically to patients with metastatic cancer to the skin. Acute, subacute and subchronic dermal studies with A-007 in adult rabbits, rats, guinea pigs and monkeys failed to demonstrate local or systemic toxicity when applied topically as a 0.25% gel. A-007 did not penetrate the dermal lymphatics and did not produce detectable levels of A-007 in the plasma when applied as a 0.25% gel topically to skin. In the above studies, topically administered A-007 stimulated local sub-epithelial and dermal lymphocyte modulation, with increased CD8+ cytotoxic lymphocytes (CTL) noted, in guinea pig skin. Generally topical A-007 is well tolerated and may have useful immune modulation properties. 

Current developer:   Tigris Pharmaceuticals, Inc.

1: Sagiraju S, Chen K, Cole RB, Jursic BS. Electrospray-ionization mass spectrometry study of cyclodextrin complexes with A007 prodrugs. Carbohydr Res. 2009 Nov 2;344(16):2167-72. Epub 2009 Jul 22. PubMed PMID: 19729153.

2: Sagiraju S, Jursic BS. NMR spectroscopic study of cyclodextrin inclusion complexes with A-007 prodrugs. Carbohydr Res. 2008 May 19;343(7):1180-90. Epub 2008 Mar 14. PubMed PMID: 18384761.

3: Eilender D, LoRusso P, Thomas L, McCormick C, Rodgers AH, Hooper CL, Tornyos K, Krementz ET, Parker S, Morgan LR. 4,4'-Dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007): a topical treatment for cutaneous metastases from malignant cancers. Cancer Chemother Pharmacol. 2006 Jun;57(6):719-26. Epub 2005 Sep 24. PubMed PMID: 16184382.

4: Morgan LR, Thangaraj K, LeBlanc B, Rodgers A, Wolford LT, Hooper CL, Fan D, Jursic BS. Design, synthesis, and anticancer properties of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and analogues. J Med Chem. 2003 Oct 9;46(21):4552-63. PubMed PMID: 14521417.

5: Morgan LR, Jursic BS, Hooper CL, Neumann DM, Thangaraj K, LeBlanc B. Anticancer activity for 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) analogues and their abilities to interact with lymphoendothelial cell surface markers. Bioorg Med Chem Lett. 2002 Dec 2;12(23):3407-11. PubMed PMID: 12419372.

6: Morgan LR, Rodgers AH, Hooper CL, Ratterree M, Soike K, Serota D, Beis R, Schwartz SL. Comparative dermal pharmacology and toxicology of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) in rodents and primates. In Vivo. 2001 Nov-Dec;15(6):479-84. PubMed PMID: 11887332.

7: Morgan LR, Rodgers AH, LeBlanc BW, Boué SM, Yang Y, Jursic BS, Cole RB. Anticancer properties for 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007)/3,7-diaminophenothiazin-5-ium double salts. Bioorg Med Chem Lett. 2001 Aug 20;11(16):2193-5. PubMed PMID: 11514168.

8: Morgan LR, Rodgers AH, Fan D, Soike K, Ratterree M, Sartin BW, Harrison TJ. Comparative preclinical toxicology and pharmacology of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) in vitro and in rodents and primates. In Vivo. 1997 Jan-Feb;11(1):29-37. PubMed PMID: 9067770.

9: Subramasnian S, Rodgers AH, Morgan LR, Soike K, Ratteree M. Relative bioavailability of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) in rats and monkeys. J Exp Ther Oncol. 1996 Jan;1(1):62-5. PubMed PMID: 9414389.

10: Rodgers AH, Subramanian S, Morgan LR Jr. High-performance liquid chromatographic determination of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone in plasma. J Chromatogr B Biomed Appl. 1995 Aug 18;670(2):365-8. PubMed PMID: 8548030.