MedKoo product information:

 Valrubicin

valrubicin is a  semisynthetic derivative of the antineoplastic anthracycline antibiotic doxorubicin. With a mechanism of action that appears to differ from doxorubicin, valrubicin is converted intracytoplasmically into N-trifluoroacetyladriamycin, which interacts with topoisomerase II, stabilizing the complex between the enzyme and DNA; consequently, DNA replication and repair and RNA and protein synthesis are inhibited and the cell cycle is arrested in the G2 phase. In addition, this agent accumulates in the cell cytoplasm where it inhibits protein kinase C (PKC). Valrubicin is less cardiotoxic than doxorubicin when administered systemically; applied topically, this agent shows excellent tissue penetration. Structurally, the trifluoro-acetyl moiety on the amino group of the glycoside and the valerate moiety appear to result in a lipophilicity that is greater than of doxorubicin, resulting in increased intracytoplasmic concentrations. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).  

Valrubicin (N-trifluoroacetyladriamycin-14-valerate, trade name Valstar) is a chemotherapy drug used to treat bladder cancer. Valrubicin is a semisynthetic analog of the anthracycline doxorubicin, and is administered by infusion directly into the bladder.
It was originally launched as Valstar in the U.S. in 1999 for intravesical therapy of Bacille Calmette-Guérin (BCG)-refractory carcinoma in situ of the urinary bladder in patients in whom cystectomy would be associated with unacceptable morbidity or mortality; however, it was voluntarily withdrawn in 2002 due to manufacturing issues.Valstar was relaunched on September 3, 2009. (The above information was directly from http://en.wikipedia.org/wiki/Valrubicin).

DRUG DESCRIPTION

Valrubicin (N-trifluoroacetyladriamycin-14-valerate), a semisynthetic analog of the anthra-cycline doxorubicin, is a cytotoxic agent with the chemical name, (2S-cis)-2-[1,2,3,4, 6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-[[2,3,6-trideoxy-3-[(trifluoroacetyl)amino]-α-L-lyxo-hexopyranosyl]oxyl]-2-naphthacenyl]-2-oxoethyl pentanoate. Valrubicin is an orange or orange-red powder that is highly lipophilic, soluble in methylene chloride, ethanol, methanol and acetone, and relatively insoluble in water. Its chemical formula is C34H36F3NO13. VALSTAR® (valrubicin) Sterile Solution for Intravesical Instillation is intended for intra-vesical administration in the urinary bladder. It is supplied as a nonaqueous solution that should be diluted before intravesical administration. Each vial of VALSTAR contains valrubicin at a concentration of 40 mg/mL in 50% polyoxyl castor oil/50% dehydrated alcohol, USP without preservatives or other additives. The solution is sterile and nonpyro-genic.

Mechanism of Action:

Valrubicin is an anthracycline that affects a variety of inter-related biological functions, most of which involve nucleic acid metabolism. It readily penetrates into cells, where it inhibits the incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests cell cycle in G2. Although valrubicin does not bind strongly to DNA, a principal mechanism of its action, mediated by valrubicin metabolites, is interference with the normal DNA breaking-resealing action of DNA topoisomerase II.

 1: Andersen SM, Rosada C, Dagnaes-Hansen F, Laugesen IG, de Darkó E, Dam TN, Stenderup K. Topical application of valrubicin has a beneficial effect on developing skin tumors. Carcinogenesis. 2010 Jun 16. [Epub ahead of print] PubMed PMID: 20554745.

2: Gofrit ON, Zorn KC, Shikanov S, Steinberg GD. Marker lesion experiments in bladder cancer--what have we learned? J Urol. 2010 May;183(5):1678-84. Epub 2010 Mar 17. Review. PubMed PMID: 20299042.

3: Rosada C, Stenderup K, de Darkó E, Dagnaes-Hansen F, Kamp S, Dam TN. Valrubicin in a topical formulation treats psoriasis in a xenograft transplantation model. J Invest Dermatol. 2010 Feb;130(2):455-63. Epub 2009 Sep 10. PubMed PMID: 19741712.

4: Smaldone MC, Gayed BA, Tomaszewski JJ, Gingrich JR. Strategies to enhance the efficacy of intravescical therapy for non-muscle invasive bladder cancer. Minerva Urol Nefrol. 2009 Jun;61(2):71-89. Review. PubMed PMID: 19451890.

5: Grossman HB, O'Donnell MA, Cookson MS, Greenberg RE, Keane TE. Bacillus calmette-guérin failures and beyond: contemporary management of non-muscle-invasive bladder cancer. Rev Urol. 2008 Fall;10(4):281-9. PubMed PMID: 19145271; PubMed Central PMCID: PMC2615101.

6: Lamm DL, McGee WR, Hale K. Bladder cancer: current optimal intravesical treatment. Urol Nurs. 2005 Oct;25(5):323-6, 331-2. Review. PubMed PMID: 16294610.

7: Perabo FG, Müller SC. New agents in intravesical chemotherapy of superficial bladder cancer. Scand J Urol Nephrol. 2005;39(2):108-16. Review. PubMed PMID: 16019763.

8: Wu S, Sun C, Pan Y. Preparative counter-current chromatography purification of valrubicin (AD-32) from crude synthetic drug using upright coil planet centrifuge with four multilayer coils connected in series. J Chromatogr A. 2005 May 27;1076(1-2):207-11. PubMed PMID: 15974091.

9: van der Heijden AG, Witjes JA. Future strategies in the diagnosis, staging and treatment of bladder cancer. Curr Opin Urol. 2003 Sep;13(5):389-95. Review. PubMed PMID: 12917515.

10: Moreno Alvarez PJ. [International therapeutics]. Farm Hosp. 2003 Mar-Apr;27(2):127-31. Spanish. PubMed PMID: 12717569.

11: Haisfield-Wolfe ME. Drug handling questioned. Urol Nurs. 2001 Jun;21(3):200; author reply 200. PubMed PMID: 11998650.

12: Randall S. Valrubicin: an alternative to radical cystectomy for carcinoma in situ of the bladder. Urol Nurs. 2001 Feb;21(1):30-1, 34-6. Review. PubMed PMID: 11998112.

13: Kuznetsov DD, Alsikafi NF, O'Connor RC, Steinberg GD. Intravesical valrubicin in the treatment of carcinoma in situ of the bladder. Expert Opin Pharmacother. 2001 Jun;2(6):1009-13. Review. PubMed PMID: 11585003.

14: Luciani LG, Neulander E, Murphy WM, Wajsman Z. Risk of continued intravesical therapy and delayed cystectomy in BCG-refractory superficial bladder cancer: an investigational approach. Urology. 2001 Sep;58(3):376-9. PubMed PMID: 11549484.

15: Oosterlinck W. Recent clinical trials in superficial bladder cancer. Curr Opin Urol. 2001 Sep;11(5):511-5. Review. PubMed PMID: 11493773.

16: Newling DW, Hetherington J, Sundaram SK, Robinson MR, Kisbenedek L. The use of valrubicin for the chemoresection of superficial bladder cancer -- a marker lesion study. Eur Urol. 2001 Jun;39(6):643-7. PubMed PMID: 11464052.

17: Kim JC, Steinberg GD. Medical management of patients with refractory carcinoma in situ of the bladder. Drugs Aging. 2001;18(5):335-44. Review. PubMed PMID: 11392442.

18: Kim JC, Steinberg GD. The limits of bacillus Calmette-Guerin for carcinoma in situ of the bladder. J Urol. 2001 Mar;165(3):745-56. Review. PubMed PMID: 11176460.

19: Wani MK, Koseki Y, Yarber RH, Sweatman TW, Ahmed A, Samant S, Hengesteg A, Israel M, Robbins KT. Rationale for intralesional valrubicin in chemoradiation of squamous cell carcinoma of the head and neck. Laryngoscope. 2000 Dec;110(12):2026-32. PubMed PMID: 11129014.

20: Klotz L. Re: Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. J Urol. 2000 Nov;164(5):1666. PubMed PMID: 11025741.

21: Masquelier M, Vitols S, Pålsson M, Mårs U, Larsson BS, Peterson CO. Low density lipoprotein as a carrier of cytostatics in cancer chemotherapy: study of stability of drug-carrier complexes in blood. J Drug Target. 2000;8(3):155-64. PubMed PMID: 10938525.

22: Patterson AL, Greenberg RE, Weems L, Bahnson R, Wajsman Z, Israel M, Sweatman T, Webber D, Gulfo J. Pilot study of the tolerability and toxicity of intravesical valrubicin immediately after transurethral resection of superficial bladder cancer. Urology. 2000 Aug 1;56(2):232-5. PubMed PMID: 10925084.

23: Baselli EC, Greenberg RE. Intravesical therapy for superficial bladder cancer. Oncology (Williston Park). 2000 May;14(5):719-29; discussion 729-31, 734, 737. Review. PubMed PMID: 10853462.

24: Marchetti A, Wang L, Magar R, Grossman HB, Lamm DL, Schellhammer PF, Erwin-Toth P. Management of patients with Bacilli Calmette-Guérin-refractory carcinoma in situ of the urinary bladder: cost implications of a clinical trial for valrubicin. Clin Ther. 2000 Apr;22(4):422-38. PubMed PMID: 10823364.

25: Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol. 2000 Mar;163(3):761-7. Erratum in: J Urol. 2008 Jan;179(1):386. PubMed PMID: 10687972.

26: Onrust SV, Lamb HM. Valrubicin. Drugs Aging. 1999 Jul;15(1):69-75; discussion 76. Review. PubMed PMID: 10459733.

27: Valrubicin for bladder cancer. Med Lett Drugs Ther. 1999 Mar 26;41(1049):32. PubMed PMID: 10232952.

28: Greenberg RE, Bahnson RR, Wood D, Childs SJ, Bellingham C, Edson M, Bamberger MH, Steinberg GD, Israel M, Sweatman T, Giantonio B, O'Dwyer PJ. Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder. Urology. 1997 Mar;49(3):471-5. PubMed PMID: 9123721.

29: Markman M, Homesley H, Norberts DA, Schink J, Abbas F, Miller A, Soper J, Teng N, Hammond N, Muggia F, Israel M, Sweatman T. Phase 1 trial of intraperitoneal AD-32 in gynecologic malignancies. Gynecol Oncol. 1996 Apr;61(1):90-3. PubMed PMID: 8626124.

30: Gerke A, Westesen K, Koch MH. Physicochemical characterization of protein-free low density lipoprotein models and influence of drug loading. Pharm Res. 1996 Jan;13(1):44-51. PubMed PMID: 8668677.

31: Westesen K, Gerke A, Koch MH. Characterization of native and drug-loaded human low density lipoproteins. J Pharm Sci. 1995 Feb;84(2):139-47. PubMed PMID: 7738790.

32: Mori A, Kennel SJ, Huang L. Immunotargeting of liposomes containing lipophilic antitumor prodrugs. Pharm Res. 1993 Apr;10(4):507-14. PubMed PMID: 8483832.

33: Chuang LF, Kung HF, Israel M, Chuang RY. Activation of human leukemia protein kinase C by tumor promoters and its inhibition by N-trifluoroacetyladriamycin-14-valerate (AD 32). Biochem Pharmacol. 1992 Feb 18;43(4):865-72. PubMed PMID: 1540240.

34: Sweatman TW, Parker RF, Israel M. Pharmacologic rationale for intravesical N-trifluoroacetyladriamycin-14-valerate (AD 32): a preclinical study. Cancer Chemother Pharmacol. 1991;28(1):1-6. PubMed PMID: 2040028.

35: Iliakis G, Lazar W. Effect of sodium chloride concentration on adriamycin and N-trifluoroacetyladriamycin-14-valerate (AD32)-induced cell killing and DNA damage in Chinese hamster V79 cells. Cancer Res. 1987 Apr 1;47(7):1853-8. PubMed PMID: 3815376.

36: Gamba-Vitalo C, Blair OC, Tritton TR, Lane PA, Carbone R, Sartorelli AC. Cytotoxicity and differentiating actions of adriamycin in WEHI-3B D+ leukemia cells. Leukemia. 1987 Mar;1(3):188-97. PubMed PMID: 3669742.

37: Niell HB, Hunter RF, Herrod HG, Israel M. Effects of N-trifluoroacetyladriamycin-14-valerate (AD-32) on human bladder tumor cell lines. Cancer Chemother Pharmacol. 1987;19(1):47-52. PubMed PMID: 3815726.

38: Silber R, Liu LF, Israel M, Bodley AL, Hsiang YH, Kirschenbaum S, Sweatman TW, Seshadri R, Potmesil M. Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II. NCI Monogr. 1987;(4):111-5. PubMed PMID: 3041237.

39: Israel M, Idriss JM, Koseki Y, Khetarpal VK. Comparative effects of adriamycin and DNA-non-binding analogues on DNA, RNA, and protein synthesis in vitro. Cancer Chemother Pharmacol. 1987;20(4):277-84. PubMed PMID: 2446792.

40: Croce AC, Prosperi E, Supino R, Bottiroli G. Anthracycline-induced inhibition of membrane permeability functions dependent on metabolic energy. Br J Cancer. 1986 Dec;54(6):943-50. PubMed PMID: 3801290; PubMed Central PMCID: PMC2001592.

41: Ganapathi R, Grabowski D, Schmidt H, Yen A, Iliakis G. Modulation of adriamycin and N-trifluoroacetyladriamycin-14-valerate induced effects on cell cycle traverse and cytotoxicity in P388 mouse leukemia cells by caffeine and the calmodulin inhibitor trifluoperazine. Cancer Res. 1986 Nov;46(11):5553-7. PubMed PMID: 3756902.

42: Constantinides PP, Inouchi N, Tritton TR, Sartorelli AC, Sturtevant JM. A scanning calorimetric study of the interaction of anthracyclines with neutral and acidic phospholipids alone and in binary mixtures. J Biol Chem. 1986 Aug 5;261(22):10196-203. PubMed PMID: 3460992.

43: Masquelier M, Vitols S, Peterson C. Low-density lipoprotein as a carrier of antitumoral drugs: in vivo fate of drug-human low-density lipoprotein complexes in mice. Cancer Res. 1986 Aug;46(8):3842-7. PubMed PMID: 3731059.

44: Krishan A, Sauerteig A, Gordon K, Swinkin C. Flow cytometric monitoring of cellular anthracycline accumulation in murine leukemic cells. Cancer Res. 1986 Apr;46(4 Pt 1):1768-73. PubMed PMID: 3948163.

45: Pearlman LF, Chuang RY, Israel M, Simpkins H. Interaction of three second-generation anthracyclines with polynucleotides, RNA, DNA, and nucleosomes. Cancer Res. 1986 Jan;46(1):341-6. PubMed PMID: 2415249.

46: Friedman HS, Schold SC Jr, Bigner DD. Chemotherapy of subcutaneous and intracranial human medulloblastoma xenografts in athymic nude mice. Cancer Res. 1986 Jan;46(1):224-8. PubMed PMID: 2415246.

47: Israel M, Potti PG, Seshadri R. Adriamycin analogues. rationale, synthesis, and preliminary antitumor evaluation of highly active DNA-nonbinding N-(trifluoroacetyl)adriamycin 14-O-hemiester derivatives. J Med Chem. 1985 Sep;28(9):1223-8. PubMed PMID: 3839851.

48: Lambertenghi-Deliliers G, Colajori E, Annaloro C, Polli EE. [Therapy of acute leukemia: contribution of the new anthracyclinic drugs]. Recenti Prog Med. 1985 Jul-Aug;76(7-8):392-7. Review. Italian. PubMed PMID: 3906794.

49: Zirvi KA, Gilani SH, Hill GJ. Embryotoxic effects of doxorubicin and N-trifluoroacetyladriamycin-14-valerate (AD-32). Teratology. 1985 Apr;31(2):247-52. PubMed PMID: 3992493.

50: Kacinski BM, Rupp WD. Interactions of the UVRABC endonuclease in vivo and in vitro with DNA damage produced by antineoplastic anthracyclines. Cancer Res. 1984 Aug;44(8):3489-92. PubMed PMID: 6378370.

51: Vitols S, Gahrton G, Peterson C. Significance of the low-density lipoprotein (LDL) receptor pathway for the in vitro accumulation of AD-32 incorporated into LDL in normal and leukemic white blood cells. Cancer Treat Rep. 1984 Mar;68(3):515-20. PubMed PMID: 6322988.

52: Zini G, Vicario GP, Lazzati M, Arcamone F. Radioactive species in rat urines and tissues after [14C] AD 32 administration. Cancer Chemother Pharmacol. 1984;12(3):154-6. PubMed PMID: 6705133.

53: Marzin D, Jasmin C, Maral R, Mathe G. Mutagenicity of eight anthracycline derivatives in five strains of Salmonella typhimurium. Eur J Cancer Clin Oncol. 1983 May;19(5):641-7. PubMed PMID: 6347692.

54: Chuang RY, Chuang LF, Kawahata RT, Israel M. Effect of N-trifluoroacetyladriamycin-14-valerate on [3H]thymidine uptake and DNA synthesis of human lymphoma cells. J Biol Chem. 1983 Jan 25;258(2):1062-5. PubMed PMID: 6822492.

55: Potmesil M, Levin M, Traganos F, Israel M, Darzynkiewicz Z, Khetarpal VK, Silber R. In vivo effects of adriamycin or N-trifluoroacetyladriamycin-14-valerate on a mouse lymphoma. Eur J Cancer Clin Oncol. 1983 Jan;19(1):109-22. PubMed PMID: 6602051.

56: Tomlinson E, Malspeis L. Concomitant adsorption and stability of some anthracycline antibiotics. J Pharm Sci. 1982 Oct;71(10):1121-5. PubMed PMID: 6958860.

57: Raz A. B16 melanoma cell variants: irreversible inhibition of growth and induction of morphologic differentiation by anthracycline antibiotics. J Natl Cancer Inst. 1982 Apr;68(4):629-38. PubMed PMID: 7040766.

58: Israel M, Potti G. Adriamycin analogues. Preparation and biological evaluation of some N-perfluoroacyl analogues of daunorubicin, adriamycin, and N-(trifluoroacetyl)adriamycin 14-valerate and their 9,10-anhydro derivatives. J Med Chem. 1982 Feb;25(2):187-91. PubMed PMID: 7057426.

59: Lampidis TJ, Johnson LV, Israel M. Effects of adriamycin on rat heart cells in culture: increased accumulation and nucleoli fragmentation in cardiac muscle v. non-muscle cells. J Mol Cell Cardiol. 1981 Oct;13(10):913-24. PubMed PMID: 7310895.

60: Schwartz HS, Kanter PM. DNA damage by anthracycline drugs in human leukemia cells. Cancer Lett. 1981 Sep;13(4):309-13. PubMed PMID: 6946856.

61: Young RC, Ozols RF, Myers CE. The anthracycline antineoplastic drugs. N Engl J Med. 1981 Jul 16;305(3):139-53. Review. PubMed PMID: 7017406.

62: Krishan A, Dutt K, Israel M, Ganapathi R. Comparative effects of adriamycin and N-trifluoroacetyladriamycin-14-valerate on cell kinetics, chromosomal damage, and macromolecular synthesis in vitro. Cancer Res. 1981 Jul;41(7):2745-50. PubMed PMID: 6972801.

63: Blum RH, Garnick MB, Israel M, Panellos GP, Henderson IC, Frei E 3rd. Preclinical rationale and phase I clinical trial of the adriamycin analog, AD 32. Recent Results Cancer Res. 1981;76:7-15. PubMed PMID: 7232854.

64: Israel M, Karkowsky AM, Khetarpal VK. Distribution of radioactivity and anthracycline-fluorescence in tissues of mice one hour after [14C]-labeled AD 32 administration. Evidence for tissue aglycone formation. Cancer Chemother Pharmacol. 1981;6(1):25-30. PubMed PMID: 6944160.

65: Wilson RG, King M, Lockwood R, McNeil M. Effects of N-trifluoroacetyl adriamycin-14-valerate (AD32) on nuclear RNA synthesis in cultured L1210 cells. Chem Biol Interact. 1980 Nov;32(3):331-7. PubMed PMID: 7428121.

66: Krishan A, Ganapathi R. Laser flow cytometric studies on the intracellular fluorescence of anthracyclines. Cancer Res. 1980 Nov;40(11):3895-900. PubMed PMID: 6937236.

67: Vecchi A, Spreafico F, Sironi M, Cairo M, Garattini S. The immunodepressive and hematotoxic activities of N-trifluoro-acetyl-adriamycin-14-valerate. Eur J Cancer. 1980 Oct;16(10):1289-96. PubMed PMID: 7202463.

68: Brox L, Gowans B, Belch A. N-trifluoroacetyladriamycin-14-valerate and adriamycin induced DNA damage in the RPMI-6410 human lymphoblastoid cell line. Can J Biochem. 1980 Sep;58(9):720-5. PubMed PMID: 7006761.

69: Chuang LF, Kawahata RT, Chuang RY. Inhibition of chicken myeloblastosis RNA polymerase II activity in vitro by N-trifluoroacetyladriamycin-14-valerate. FEBS Lett. 1980 Aug 11;117(1):247-51. PubMed PMID: 7409170.

70: Abbruzzi R, Rizzardini M, Benigni A, Barbieri B, Donelli MG, Salmona M. Possible relevance of N-trifluoroacetyladriamycin (AD 41) in the antitumoral activity of N-trifluoroacetyladriamycin-14-valerate (AD 32) in tumor-bearing mice. I. Pharmacokinetic evidence. Cancer Treat Rep. 1980 Aug-Sep;64(8-9):873-8. PubMed PMID: 7448825.

71: Israel M, Karkowsky AM, Pegg WJ. Pharmacologic studies with radiolabeled N-trifluoroacetyladriamycin-14-valerate (AD 32). Comparison of total anthracycline fluorescence and radioactivity in mouse serum and urine. Cancer Chemother Pharmacol. 1980;4(2):79-82. PubMed PMID: 7389059.

72: Seeber S, Loth H, Crooke ST. Comparative nuclear and cellular incorporation of daunorubicin, doxorubicin, carminomycin, marcellomycin, aclacinomycin A and AD 32 in daunorubicin-sensitive and -resistant Ehrlich ascites in vitro. J Cancer Res Clin Oncol. 1980;98(2):109-18. PubMed PMID: 6938517.