title: Inhibition of Cathepsin S by Fsn0503 enhances the efficacy of chemotherapy in colorectal carcinomas.
abstract: Cathepsin S is a lysosomal cysteine protease implicated in tumourigenesis with key roles in invasion and angiogenesis. We have previously shown that the specific inhibition of Cathepsin S using a monoclonal antibody (Fsn0503) blocks colorectal carcinoma tumour growth and angiogenesis in vivo. We investigated whether Cathepsin S expression levels were affected by chemotherapy in human cancer cell lines by RT-PCR. Using colorectal xenograft models, we examined the therapeutic benefit of Cathepsin S inhibition using Fsn0503 in combination with a metronomic dosing regimen of CPT-11. We analysed the effects of the combination therapy on tumour progression and on tumour vascularisation by immunohistochemical staining of tumours. Cathepsin S expression levels are upregulated in HCT116, LoVo, Colo205 cell lines and HUVECs after exposure to CPT-11 in vitro. The administration of Fsn0503 in combination with CPT-11 significantly attenuated tumour growth in comparison to CPT-11 alone in colorectal HCT116 xenograft models. Furthermore, analysis of tumour vascularisation revealed that this was also significantly disrupted by the combination treatment. These results show that the combination of Cathepsin S inhibition with CPT-11 enhances the therapeutic effect of the chemotherapy. This rationale may have clinical application in the treatment of colorectal cancer upon further evaluation.
authors: Fusion Antibodies Ltd., Springbank Industrial Estate, Pembroke Loop Road, Belfast BT17 0QL, UK.
authors: Roberta E
authors: RE
authors: Burden
authors: Julie A
authors: JA
authors: Gormley
authors: Diana
authors: D
authors: Kuehn
authors: Claire
authors: C
authors: Ward
authors: Hang Fai
authors: HF
authors: Kwok
authors: Mihaela
authors: M
authors: Gazdoiu
authors: Angela
authors: A
authors: McClurg
authors: Thomas J
authors: TJ
authors: Jaquin
authors: James A
authors: JA
authors: Johnston
authors: Christopher J
authors: CJ
authors: Scott
authors: Shane A
authors: SA
authors: Olwill
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003106:Colon / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D015853:Cysteine Proteinase Inhibitors; D000077146:Irinotecan; D002403:Cathepsins; C028217:cathepsin S; D002166:Camptothecin