Antitumor effects of telomelysin in combination with paclitaxel or cisplatin on head and neck squamous cell carcinoma.
Telomelysin (OBP-301) is a telomerase-specific replication-component adenovirus. Telomelysin has a human telomerase reverse transcriptase (hTERT) promoter element which efficiently kills human cancer cells, but not normal cells. The present study investigated the correlation between the antitumor effect of telomelysin and mRNA expression of hTERT and coxsackievirus and adenovirus receptor (CAR) in head and neck squamous cell carcinoma (HNSCC) in vitro and whether telomelysin enhances the antitumor effect of paclitaxel or cisplatin, in vivo using a HNSCC xenograft model. We also determined the optimal order for combining telomelysin treatment and chemotherapy as concurrent treatment, telomelysin treatment first and chemotherapy later, chemotherapy first and telomelysin treatment later for achieving the best anticancer effect. The mRNA expression of hTERT and CAR genes was examined by quantitative RT-PCR in 17 HNSCC cell lines. There was no significant correlation between the growth inhibition of telomelysin (ID50 for day 3, 5 and 7) in vitro and mRNA expression levels of hTERT and CAR. Regarding the correlation between CAR expression and telomelysin ID50 for day 3, all cell lines that showed a relative amount of CAR/beta-actin mRNA >0.4 had a low telomelysin ID50. This may indicate that CAR expression contributes to the efficacy of adenovirus infection and the antitumor activity of telomelysin in early stages of treatment. In our in vivo study, combining telomelysin and paclitaxel had an additive effect regardless of treatment order. On the other hand, combining telomelysin and cisplatin had additive effect only when cisplatin treatment preceded telomelysin treatment. These results suggest that paclitaxel is considered innocuous for replication of telomelysin, however cisplatin may influence replication of telomelysin.
Kondo
Norio
N
Department of Biology and Function in Head and Neck, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan. t076022c@yokohama-cu.ac.jp
Tsukuda
Mamoru
M
Kimura
Machiko
M
Fujita
Kyoko
K
Sakakibara
Atsuko
A
Takahashi
Hideaki
H
Ishiguro
Yukari
Y
Toth
Gabor
G
Matsuda
Hideki
H
D000256:Adenoviridae / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy*; D002945:Cisplatin / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D005260:Female; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology*; D017239:Paclitaxel / Q000008:administration & dosage*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019098:Telomerase / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C509186:TERT protein, human; D019098:Telomerase; D017239:Paclitaxel; D002945:Cisplatin