Cidofovir incorporation into human keratinocytes with episomal HPV 16 results in nonselective cytotoxicity.
OBJECTIVE
Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV). Surgical excision is the mainstay of treatment; however, medical therapy including cidofovir, a cytosine analog, has been investigated. Human papillomavirus does not encode a viral DNA polymerase, which is the known target of cidofovir in cytomegalovirus infections.


METHODS
In an effort to better understand the usefulness of cidofovir in the treatment of HPV-related disease, we tested cidofovir's ability to inhibit growth, alter gene expression, and inhibit genome replication.


RESULTS
With the use of carbon 14-labeled cidofovir in episomal HPV 16-containing keratinocytes, there was a minimal increase in cidofovir incorporation into episomal DNA versus genomic DNA. Cidofovir decreased the copies of episomal HPV 16 in keratinocytes; however, the copies per cell returned to baseline levels once cidofovir was removed. Expression of a viral oncogene (HPV 16 E6) in transformed keratinocytes with episomal HPV 16 was not decreased by cidofovir. Cytotoxicity in head and neck squamous cell carcinoma lines exposed to cidofovir correlated with cell doubling time, and not with HPV status. Also, tonsil keratinocytes transformed with episomal HPV 16 did not exhibit greater cidofovir-mediated toxicity than did telomerase-transformed keratinocytes.


CONCLUSIONS
These findings suggest that any potential in vivo benefit of cidofovir therapy results from non-viral-specific cell toxicity at the site of application.
Spanos
William C
WC
Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.
El-Deiry
Mark
M
Lee
John H
JH
D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005814:Genes, Viral / Q000187:drug effects; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000821:virology*; D063065:Organophosphonates / Q000493:pharmacokinetics* / Q000494:pharmacology; D010957:Plasmids; D014407:Tumor Cells, Cultured
D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir