title: Chemotherapy counteracts metastatic dissemination induced by antiangiogenic treatment in mice.
abstract: The development of resistance and progressive disease after treatment with angiogenesis inhibitors is becoming a controversial issue. We investigated the experimental conditions that cause multireceptor tyrosine kinase inhibitors (RTKI) to augment metastasis and whether opportune combinations with chemotherapy could counteract this effect. The renal Renca-luc tumor was transplanted orthotopically in the kidney of Balb/c mice, which then were or were not nephrectomized. The Lewis Lung carcinoma (LLC) was transplanted in the tibial muscle of C57/Bl6 mice. Treatment with the RTKI sunitinib started at different stages of tumor progression, mimicking neoadjuvant or adjuvant settings. Combination studies with paclitaxel, doxorubicin, cisplatin, gemcitabine, and topotecan were done on the LLC model, using opportune regimens. In a neoadjuvant setting, sunitinib inhibited Renca-luc tumor growth, prolonging survival despite an increase in lung metastasis; treatment after primary tumor surgery (adjuvant setting) or on established metastasis prolonged survival and decreased metastasis. Sunitinib increased lung metastasis from mice bearing early-stage LLC, but did not affect established metastases (no acceleration) from advanced tumors. Combinations with doxorubicin, topotecan, gemcitabine, but not cisplatin and paclitaxel, counteracted the increase in metastasis from LLC, partly reflecting their antitumor activity. Histology analysis after sunitinib confirmed tumor vascular changes and increased hypoxia. Topotecan at suboptimal daily doses reduced sunitinib-related metastasis, reducing tumor hypoxia. Tyrosine kinase inhibitors, as sunitinib, can have adverse malignant effects mainly in the neoadjuvant setting. The addition of chemotherapy might influence metastasis, depending on each drug mechanism of action and its regimen of administration.
authors.affiliation: Corresponding Author: Raffaella Giavazzi, Laboratory of Biology and Treatment of Metastasis, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy. raffaella.giavazzi@marionegri.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rovida
authors.forename: Vittoria
authors.initials: V
authors.lastname: Castiglioni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Decio
authors.forename: Valentina
authors.initials: V
authors.lastname: Scarlato
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scanziani
authors.forename: Raffaella
authors.initials: R
authors.lastname: Giavazzi
authors.forename: Marta
authors.initials: M
authors.lastname: Cesca
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004317:Doxorubicin / Q000008:administration & dosage; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D000077210:Sunitinib; D019772:Topotecan / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D003841:Deoxycytidine; D019772:Topotecan; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin; D000077210:Sunitinib; D000093542:Gemcitabine