Proliferative Verrucous Leukoplakia Medication
- Author: Rahat S Azfar, MD; Chief Editor: Dirk M Elston, MD more...
Antineoplastic Agent, Antibiotic
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
Klanrit P, Sperandio M, Brown AL, et al. DNA ploidy in proliferative verrucous leukoplakia. Oral Oncol. 2007 Mar. 43(3):310-6. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
Batsakis JG, Suarez P, el-Naggar AK. Proliferative verrucous leukoplakia and its related lesions. Oral Oncol. 1999 Jul. 35(4):354-9. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
Haley JC, Hood AF, Mirowski GW. Proliferative verrucous leukoplakia with cutaneous involvement. J Am Acad Dermatol. 1999 Sep. 41(3 Pt 1):481-3. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
Greer RO. Pathology of malignant and premalignant oral epithelial lesions. Otolaryngol Clin North Am. 2006 Apr. 39(2):249-75, v. [Medline].
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. [Medline].
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. [Medline].