melphalan and Tonsillar-Neoplasms

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

Topics: Adolescent; Aged; Bone Neoplasms; Female; Hemangiosarcoma; Hodgkin Disease; Humans; Leukopenia; Lymphoma, Large B-Cell, Diffuse; Male; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Sarcoma, Ewing; Testicular Neoplasms; Thrombocytopenia; Tonsillar Neoplasms; Uterine Neoplasms

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Chlorpromazine; Cyclophosphamide; Female; Fever; Humans; Liver Neoplasms; Lymphatic Metastasis; Lymphoma, Large B-Cell, Diffuse; Male; Mechlorethamine; Melphalan; Middle Aged; Nasopharyngeal Neoplasms; Nausea; Neoplasm Recurrence, Local; Olivomycins; Thiotepa; Thrombocytopenia; Tonsillar Neoplasms; Vomiting