Potential risk factors associated with the use of cidofovir to treat benign human papillomavirus-related disease.
BACKGROUND
Cidofovir is currently being used off-licence to treat different viral infections, such as benign low-risk human papillomavirus (HPV)-related recurrent respiratory papillomatosis (RRP). There are concerns over the safety of this practice as rat studies demonstrated a high malignant transformation rate. As yet, there are no clinical reports of cidofovir-induced malignant changes in humans.


METHODS
Telomerase immortalised human keratinocytes (hTert) stably expressing E6 proteins from either low-risk HPV6b or high-risk HPV16 and vector control cells were treated with either low-dose (5 microg/ml) or higher dose (30 microg/ml) cidofovir for 2 days and the effects evaluated by clonogenic survival assays. Based on these results, gene expression microarray analysis was performed on cidofovir-treated low-risk E6 and vector cells before, during and after drug treatment, and the results verified by real-time PCR.


RESULTS
Both low-risk and high-risk E6-expressing cells show significantly improved long-term survival compared with vector control cells when exposed to 5 microg/ml cidofovir for 2 days, (hTert T6E6 P=0.0007, hTert T16E6 P=0.00023 and hTert vector control P=0.62). Microarray and real-time PCR analyses of low-dose cidofovir-treated low-risk E6-expressing cells revealed changes in gene expression that are known to be associated with malignant progression, which were not observed in drug-treated vector control cells.


CONCLUSIONS
This is the first report that cidofovir can both increase cell survival and induce alterations in gene expression that are known to be associated with malignant transformation in cells transduced only with the E6 gene from low-risk HPV. It is our belief that these data provide cause for concern over the off-license use of this drug to treat RRP.
Donne
Adam J
AJ
Department of Otolaryngology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK. ajdonne@doctors.org.uk
Hampson
Lynne
L
He
Xiaotong T
XT
Day
Philip J R
PJ
Salway
Fiona
F
Rothera
Michael P
MP
Homer
Jarrod J
JJ
Hampson
Ian N
IN
D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D056687:Off-Label Use; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D010212:Papilloma / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D027383:Papillomaviridae / Q000187:drug effects; D030361:Papillomavirus Infections / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D012313:RNA / Q000096:biosynthesis; D012142:Respiratory Tract Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D012307:Risk Factors
D000998:Antiviral Agents; D063065:Organophosphonates; D012313:RNA; D003596:Cytosine; D000077404:Cidofovir