Antineoplastic Agent, Antibiotic

Bleomycin (Blenoxane)

View full drug information

This agent consists of a group of glycopeptides extracted from Streptomyces species. Each molecule has a planar end and an amine end; different glycopeptides of the group differ in their terminal amine moieties. The planar end intercalates with DNA, while the amine end facilitates oxidation of bound ferrous ions to ferric ions, thereby generating free radicals, which subsequently cleave DNA, acting specifically at purine-G-C-pyrimidine sequences.

It is not absorbed when given orally; peak levels are reached in approximately 30-60 min when given intramuscularly and are only one third of the levels obtained after intravenous administration; approximately 50% of the drug is absorbed systemically after intrapleural or intraperitoneal administration; systemic absorption after intracavitary administration for craniopharyngioma not negligible.

The volume of distribution is 20-30 L, both in intracellular and extracellular fluid. Less than 10% is bound to plasma proteins.

Bleomycin has plasma half-life of more than 1 hour and a terminal half-life of 2-4 hours, but it could be as long as 22 hours in patients with renal dysfunction or those previously treated with cisplatin.

Approximately 50% is eliminated in the urine within 24 hours. Most tissues (known exceptions—skin and lungs) contain an enzyme, bleomycin hydrolase (most active tissues are liver and kidney), which readily inactivates the drug; therefore, toxicity is tissue specific, occurring in tissues lacking this enzyme. Bleomycin is mostly used systemically in combination with other drugs (mostly with cisplatin and vincristine).

The principal mechanisms of resistance include high levels of bleomycin hydrolase, cell mutations altering DNA sequences to prevent intercalation, poor cell accumulation of the drug, and rapid plasma removal. None of these factors plays an important role when bleomycin is administered locally in a residual cyst.

Toxicity is age dependent and cumulative-dose related; systemic administration mostly causes pulmonary toxicity. This consists of pneumonitis, which can progress to fatal pulmonary fibrosis.

The maximum recommended total cumulative dose for systemic use is 400 U. Unit measurement is based on toxicity to bacteria; 1 U equals approximately 1.7 mg.

Administered systemically, bleomycin does not produce significant bone marrow toxicity. Toxicity with local administration is due to both systemic contamination (when anaphylactoid reactions, transient fever, nausea, and vomiting could occur) and leakage into surrounding neural tissue. Fatal outcomes have been reported with leakage, owing to subsequent diffuse diencephalon and brainstem edema.

Contrast CT cystography is required prior to intracavitary administration to ensure cyst wall integrity; when inconclusive, MR cystography with gadopentetate dimeglumine has been advocated.

Palefsky JM, Silverman S Jr, Abdel-Salaam M, Daniels TE, Greenspan JS. Association between proliferative verrucous leukoplakia and infection with human papillomavirus type 16. J Oral Pathol Med. 1995 May. 24(5):193-7. [QxMD MEDLINE Link].
Bagan JV, Jimenez Y, Murillo J, et al. Lack of association between proliferative verrucous leukoplakia and human papillomavirus infection. J Oral Maxillofac Surg. 2007 Jan. 65(1):46-9. [QxMD MEDLINE Link].
Campisi G, Giovannelli L, Ammatuna P, et al. Proliferative verrucous vs conventional leukoplakia: no significantly increased risk of HPV infection. Oral Oncol. 2004 Sep. 40(8):835-40. [QxMD MEDLINE Link].
Bagan JV, Jimenez Y, Murillo J, et al. Epstein-Barr virus in oral proliferative verrucous leukoplakia and squamous cell carcinoma: A preliminary study. Med Oral Patol Oral Cir Bucal. 2008 Feb 1. 13(2):E110-3. [QxMD MEDLINE Link].
Aguirre-Urizar JM. Proliferative multifocal leukoplakia better name that proliferative verrucous leukoplakia. World J Surg Oncol. 2011 Oct 10. 9:122. [QxMD MEDLINE Link]. [Full Text].
Kresty LA, Mallery SR, Knobloch TJ, et al. Frequent alterations of p16INK4a and p14ARF in oral proliferative verrucous leukoplakia. Cancer Epidemiol Biomarkers Prev. 2008 Nov. 17(11):3179-87. [QxMD MEDLINE Link].
Gopalakrishnan R, Weghorst CM, Lehman TA, et al. Mutated and wild-type p53 expression and HPV integration in proliferative verrucous leukoplakia and oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997 Apr. 83(4):471-7. [QxMD MEDLINE Link].
Kannan R, Bijur GN, Mallery SR, et al. Transforming growth factor-alpha overexpression in proliferative verrucous leukoplakia and oral squamous cell carcinoma: an immunohistochemical study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996 Jul. 82(1):69-74. [QxMD MEDLINE Link].
Kahn MA, Dockter ME, Hermann-Petrin JM. Proliferative verrucous leukoplakia. Four cases with flow cytometric analysis. Oral Surg Oral Med Oral Pathol. 1994 Oct. 78(4):469-75. [QxMD MEDLINE Link].
Klanrit P, Sperandio M, Brown AL, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007 Mar. 43(3):310-6. [QxMD MEDLINE Link].
Hansen LS, Olson JA, Silverman S Jr. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985 Sep. 60(3):285-98. [QxMD MEDLINE Link].
Bagan JV, Murillo J, Poveda R, Gavalda C, Jimenez Y, Scully C. Proliferative verrucous leukoplakia: unusual locations of oral squamous cell carcinomas, and field cancerization as shown by the appearance of multiple OSCCs. Oral Oncol. 2004 Apr. 40(4):440-3. [QxMD MEDLINE Link].
Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996 Oct. 82(4):396-401. [QxMD MEDLINE Link].
Silverman S Jr, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997 Aug. 84(2):154-7. [QxMD MEDLINE Link].
Batsakis JG, Suarez P, el-Naggar AK. Proliferative verrucous leukoplakia and its related lesions. Oral Oncol. 1999 Jul. 35(4):354-9. [QxMD MEDLINE Link].
Ghazali N, Bakri MM, Zain RB. Aggressive, multifocal oral verrucous leukoplakia: proliferative verrucous leukoplakia or not?. J Oral Pathol Med. 2003 Aug. 32(7):383-92. [QxMD MEDLINE Link].
Bagan JV, Jiménez-Soriano Y, Diaz-Fernandez JM, Murillo-Cortés J, Sanchis-Bielsa JM, Poveda-Roda R, et al. Malignant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol. 2011 Aug. 47(8):732-5. [QxMD MEDLINE Link].
Gouvêa AF, Moreira AE, Reis RR, de Almeida OP, Lopes MA. Proliferative verrucous leukoplakia, squamous cell carcinoma and axillary metastasis. Med Oral Patol Oral Cir Bucal. 2010 Sep 1. 15(5):e704-8. [QxMD MEDLINE Link].
Cerero-Lapiedra R, Baladé-Martínez D, Moreno-López LA, Esparza-Gómez G, Bagán JV. Proliferative verrucous leukoplakia: a proposal for diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2010 Nov 1. 15(6):e839-45. [QxMD MEDLINE Link].
Morton TH, Cabay RJ, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: report of three cases. J Oral Pathol Med. 2007 May. 36(5):315-8. [QxMD MEDLINE Link].
Bagan JV, Jimenez Y, Sanchis JM, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003 Aug. 32(7):379-82. [QxMD MEDLINE Link].
Abadie WM, Partington EJ, Fowler CB, Schmalbach CE. Optimal Management of Proliferative Verrucous Leukoplakia: A Systematic Review of the Literature. Otolaryngol Head Neck Surg. 2015 Oct. 153 (4):504-11. [QxMD MEDLINE Link].
Haley JC, Hood AF, Mirowski GW. Proliferative verrucous leukoplakia with cutaneous involvement. J Am Acad Dermatol. 1999 Sep. 41(3 Pt 1):481-3. [QxMD MEDLINE Link].
Gouvêa AF, Vargas PA, Coletta RD, Jorge J, Lopes MA. Clinicopathological features and immunohistochemical expression of p53, Ki-67, Mcm-2 and Mcm-5 in proliferative verrucous leukoplakia. J Oral Pathol Med. 2010 Jul. 39(6):447-52. [QxMD MEDLINE Link].
Gouvêa AF, Santos Silva AR, Speight PM, Hunter K, Carlos R, Vargas PA, et al. High incidence of DNA ploidy abnormalities and increased Mcm2 expression may predict malignant change in oral proliferative verrucous leukoplakia. Histopathology. 2013 Mar. 62 (4):551-62. [QxMD MEDLINE Link].
Flores IL, Santos-Silva AR, Coletta RD, Leme AF, Lopes MA. Low expression of angiotensinogen and dipeptidyl peptidase 1 in saliva of patients with proliferative verrucous leukoplakia. World J Clin Cases. 2016 Nov 16. 4 (11):356-363. [QxMD MEDLINE Link].
Cabay RJ, Morton TH Jr, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: a review of the literature. J Oral Pathol Med. 2007 May. 36(5):255-61. [QxMD MEDLINE Link].
Vigliante CE, Quinn PD, Alawi F. Proliferative verrucous leukoplakia: report of a case with characteristic long-term progression. J Oral Maxillofac Surg. 2003 May. 61(5):626-31. [QxMD MEDLINE Link].
Greer RO. Pathology of malignant and premalignant oral epithelial lesions. Otolaryngol Clin North Am. 2006 Apr. 39(2):249-75, v. [QxMD MEDLINE Link].
Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, Naranjo-Diaz MJ, Aneiros-Fernandez J, Ruiz-Villaverde R, et al. Successful treatment of proliferative verrucous leukoplakia with 5% topical imiquimod. Dermatol Ther. 2017 Mar. 30 (2):[QxMD MEDLINE Link].
Schoelch ML, Sekandari N, Regezi JA, Silverman S Jr. Laser management of oral leukoplakias: a follow-up study of 70 patients. Laryngoscope. 1999 Jun. 109(6):949-53. [QxMD MEDLINE Link].
Bombeccari GP, Garagiola U, Candotto V, Pallotti F, Carinci F, Giannì AB, et al. Diode laser surgery in the treatment of oral proliferative verrucous leukoplakia associated with HPV-16 infection. Maxillofac Plast Reconstr Surg. 2018 Dec. 40 (1):16. [QxMD MEDLINE Link].
Femiano F, Gombos F, Scully C. Oral proliferative verrucous leukoplakia (PVL); open trial of surgery compared with combined therapy using surgery and methisoprinol in papillomavirus-related PVL. Int J Oral Maxillofac Surg. 2001 Aug. 30(4):318-22. [QxMD MEDLINE Link].

Media Gallery

A leukokeratotic plaque is seen in on the upper lip, along with an erythematous plaque on the left hard palate. The patient has a large right-palate defect from a prior surgical excision of a squamous cell carcinoma.

of 1

Author

Rahat S Azfar, MD Clinical Instructor, Department of Dermatology, University of Pennsylvania Health System

Rahat S Azfar, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for Dermatologic Surgery, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Coauthor(s)

Fatima A Abdulla, MD Associated Staff Physician, Department of Dermatology, Cleveland Clinic Abu Dhabi, UAE

Fatima A Abdulla, MD is a member of the following medical societies: European Academy of Dermatology and Venereology, Jordan Medical Association, Jordanian Society of Dermatology and Venereology

Disclosure: Nothing to disclose.

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Specialty Editor Board

David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Military Dermatologists, Phi Beta Kappa, Texas Dermatological Society

Disclosure: Nothing to disclose.

Rosalie Elenitsas, MD Herman Beerman Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Rosalie Elenitsas, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society of Dermatopathology, Pennsylvania Academy of Dermatology

Disclosure: Received royalty from Lippincott Williams Wilkins for textbook editor.

Chief Editor

Jeff Burgess, DDS, MSD (Retired) Clinical Assistant Professor, Department of Oral Medicine, University of Washington School of Dental Medicine; (Retired) Attending in Pain Center, University of Washington Medical Center; (Retired) Private Practice in Hawaii and Washington; Director, Oral Care Research Associates

Disclosure: Nothing to disclose.

Additional Contributors

Jacek C Szepietowski, MD, PhD Professor, Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University; Director of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Poland

Disclosure: Received consulting fee from Orfagen for consulting; Received consulting fee from Maruho for consulting; Received consulting fee from Astellas for consulting; Received consulting fee from Abbott for consulting; Received consulting fee from Leo Pharma for consulting; Received consulting fee from Biogenoma for consulting; Received honoraria from Janssen for speaking and teaching; Received honoraria from Medac for speaking and teaching; Received consulting fee from Dignity Sciences for consulting; .