Augmented antitumour effects of combination therapy with TNP-470 and chemoimmunotherapy in mice.
OBJECTIVE
To investigate antitumour efficacy of the combination of the antiangiogenic agent TNP-470 combined with chemoimmunotherapy in different tumour models in mice


METHODS
B6D2F1 mice and BALB/c mice were inoculated in the footpad of the right hind limb with B16F10 melanoma cells or colon adenocarcinoma cells C-26, respectively. Subsequently, they received therapy consisting of TNP-470 and/or IL-12 and tumour growth was observed. In the melanoma model this therapy regimen was combined with cisplatin in a subtherapeutic dose. The antiangiogenic action of the tested agents was evaluated using tumour-induced angiogenesis assay in vivo. In order to analyse interactions between TNP-470 (or cisplatin) and IFN-gamma on tumour cells in vitro, the following methods were used: MTT assay, Western blot analysis, and flow cytometry analysis.


RESULTS
Administration of the combined therapy with TNP-470 and IL-12 resulted in augmented antitumour activity in colon-26 and B16F10 melanoma models. Addition of cisplatin further enhanced efficacy of this combined therapy in the melanoma model. We showed that antitumour activity of this combined therapy is mediated by multiple mechanisms: not only is enhancement of the antiangiogenic activity mediated by TNP-470 and IL-12 but also by the synergistic cytostatic/cytotoxic action of IL-12-induced IFN-gamma and TNP-470 or cisplatin on tumour cells. The experiments revealed that TNP-470 together with IFN-gamma leads to the increased expression of p21 protein in cancer cells, which in turn may contribute to their cytostatic/cytotoxic action in vitro.


CONCLUSIONS
Our experiments show a successful TNP-470-based combination therapy and suggest that the enhancement of the antitumour activity could be explained by a concomitant effect on both endothelial and tumour cell compartments.
Department of Lymphoproliferative Diseases, Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland.
Anna
A
Dabrowska-Iwanicka
Dominika
D
Olszewska
Ahmad
A
Jalili
Marcin
M
Makowski
Tomasz
T
Grzela
Maria
M
Marczak
Grazyna
G
Hoser
Adam
A
Giermasz
Jakub
J
Golab
Marek
M
Jakóbisiak
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D052160:Benzothiazoles; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology; D002945:Cisplatin / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D003510:Cyclohexanes; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000627:therapeutic use; D013778:Tetrazolium Salts; D013844:Thiazoles / Q000008:administration & dosage; D014050:Toluene / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D052160:Benzothiazoles; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003510:Cyclohexanes; D012717:Sesquiterpenes; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D018664:Interleukin-12; D014050:Toluene; D007371:Interferon-gamma; C121565:pifithrin; C022616:thiazolyl blue; D002945:Cisplatin; D000077609:O-(Chloroacetylcarbamoyl)fumagillol