The novel DNA alkylating agent BO-1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

• Published in: International journal of cancer 2012-03, Vol.130 (6), p.1440-1450
• Main Authors: Sanjiv, Kumar, Su, Tsann-Long, Suman, Sharda, Kakadiya, Rajesh, Lai, Tsung-Ching, Wang, Hsuan-Yao, Hsiao, Michael, Lee, Te-Chang
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Alkylating agents; Alkylating Agents - pharmacology; Animal models; Animals; anticancer; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Bromodeoxyuridine; Cancer; Cancer therapies; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell culture; Cell Cycle Checkpoints - drug effects; Cell Growth Processes - drug effects; Cell Line; Cell Line, Tumor; Chemotherapy; CHO Cells; Cisplatin; Comet assay; Cricetinae; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA - drug effects; DNA biosynthesis; DNA Damage; DNA interstrand crosslinks; Fibroblasts - drug effects; G1 Phase - drug effects; Head & neck cancer; human oral cancer; Humans; Indene; KB Cells; Medical research; Medical sciences; Mice; Mouth; Mouth Neoplasms - drug therapy; Mouth Neoplasms - genetics; Mouth Neoplasms - pathology; novel DNA alkylating agent; Oral cancer; Oral carcinoma; Oral cavity; orthotopic mouse models; Otorhinolaryngology. Stomatology; Radiation therapy; S Phase - drug effects; Tumor cell lines; Tumors; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology; xenografted; Xenografts
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.26142

Oral cancer is the fourth‐most common cause of death in males and overall the sixth‐most common cause of cancer death in Taiwan. Surgery, radiotherapy and chemotherapy combined with other therapies are the most common treatments for oral cavity cancer. Although cisplatin, 5‐fluorouracil and docetaxel are commonly used clinically, there is no drug specific for oral cavity cancer. Here, we demonstrated that derivatives of 3a‐aza‐cyclopenta[a]indene, a class of newly synthesized alkylating agents, may be drugs more specific for oral cancer based on its potent in vitro cytotoxicity to oral cancer cells and on in vivo xenografts. Among them, BO‐1090, bis(hydroxymethyl)‐3a‐aza‐cyclopenta[a]indene derivative, targeted DNA for its cytotoxic effects as shown by inhibition of DNA synthesis (bromodeoxyuridine‐based DNA synthesis assay), induction of DNA crosslinking (alkaline gel shift assay), and induction of DNA single‐stranded breaks (Comet assay) and double‐stranded breaks (γ‐H2AX focus formation). Following DNA damage, BO‐1090 induced G1/S‐phase arrest and apoptosis in oral cancer cell lines. The therapeutic potential of BO‐1090 was tested in mice that received a xenograft of oral cavity cancer cell lines (SAS or Cal 27 cells). Intravenous injection of BO‐1090 significantly suppressed tumor growth in comparison to control mice. BO‐1090 also significantly reduced the tumor burden in orthotopic mouse models using SAS cells. There was no significant adverse effect of BO‐1090 treatment with this dosage based on whole blood count, biochemical enzyme profiles in plasma and histopathology of various organs in mouse. Taken together, our current results demonstrate that B0‐1090 may have potential as a treatment for oral cavity cancer.