melphalan and Papillomavirus-Infections

Here we show that treatment of the HPV16-positive tonsillar cancer cell line HN26 with DNA alkylating cancer drug melphalan-induced p53 and activated apoptosis. Melphalan reduced the levels of RNA polymerase II and cellular transcription factor Sp1 that were associated with HPV16 DNA. The resulting inhibition of transcription caused a rapid loss of the HPV16 early mRNAs encoding E6 and E7 as a result of their inherent instability. As a consequence of HPV16 E6 and E7 down-regulation, the DNA damage inflicted on the cells by melphalan caused induction of p53 and activation of apoptosis in the HN26 cells. The BARD1-negative phenotype of the HN26 cells may have contributed to the failure to repair DNA damage caused by melphalan, as well as to the efficient apoptosis induction. Finally, nude mice carrying the HPV16 positive tonsillar cancer cells responded better to melphalan than to cisplatin, the chemotherapeutic drug of choice for tonsillar cancer. We concluded that the short half-life of the HPV16 E6 and E7 mRNAs renders HPV16-driven tonsillar cancer cells particularly sensitive to DNA damaging agents such as melphalan since melphalan both inhibits transcription and causes DNA damage.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Cell Line, Tumor; Half-Life; Human papillomavirus 16; Humans; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Oncogene Proteins, Viral; Papillomavirus E7 Proteins; Papillomavirus Infections; Repressor Proteins; RNA Stability; Squamous Cell Carcinoma of Head and Neck; Tonsillar Neoplasms; Xenograft Model Antitumor Assays

HPV oncoproteins are selectively retained and expressed in HPV infected carcinoma cells. The E7 oncoprotein interacts with the tumour suppressor Rb, and leads to the progression of oncogenesis. In a previous study, E7 biomarkers were identified in E7 Tg mice. In this study, in order to investigate whether a genotoxic carcinogen would modulate carcinogenesis in the E7-Tg mice, an anticancer drug, melphalan, was intraperitoneally injected into E7-Tg mice for eight weeks at two-day intervals and then genes and proteins were analysed using Omics approaches and RT-qPCR. RT-qPCR was performed to confirm whether E7 biomarkers would be modulated by melphalan treatment in E7-Tg mice, revealing that up-regulated E7 markers such as cyclin B1, CD166, and actin alpha1 were down-regulated, whereas expression of down-regulated E7 markers such as vimentin was restored by melphalan treatment. These results suggest that melphalan inhibits carcinogenesis via modulating E7-specific genes and proteins expressed in the lung tissues of E7 Tg mice.

Topics: Actins; Activated-Leukocyte Cell Adhesion Molecule; Animals; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Cyclin B1; Down-Regulation; Female; Injections, Intraperitoneal; Lung; Lung Neoplasms; Male; Melphalan; Mice; Mice, Transgenic; Papillomavirus E7 Proteins; Papillomavirus Infections; Reverse Transcriptase Polymerase Chain Reaction

We describe the previously unreported use of isolated limb infusion (ILI) to treat extensive, bilateral plantar warts in a 54-year-old female. The warts had covered the weight-bearing surfaces of both feet for 10 years and had failed to respond to all previous treatments.. A standard ILI technique was used to infuse melphalan and actinomycin D to the left leg. Circulation was maintained for 30 min. The limb was warmed and upon completion of the procedure was markedly hypoxic and acidotic. The contralateral limb was treated 6 months later.. At 5 weeks, a partial response with 80% disease clearance was observed. Pain impeded mobilisation until desquamation occurred 6 weeks postoperatively. There was little regrowth at 6 months.. Although invasive, ILI may represent a viable treatment option for resistant human papilloma virus-induced warts on the peripheries. Further research into this potential treatment tool is warranted.

Topics: Cytotoxins; Dactinomycin; Drug Therapy, Combination; Female; Foot Dermatoses; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Infusions, Parenteral; Melphalan; Middle Aged; Papillomavirus Infections; Warts