title: Single low-dose cyclophosphamide combined with interleukin-12 gene therapy is superior to a metronomic schedule in inducing immunity against colorectal carcinoma in mice.
abstract: The use of conventional cytotoxic agents at metronomic schedules, alone or in combination with targeted agents or immunotherapy, is being explored as a promising anticancer strategy. We previously reported a potent antitumor effect of a single low-dose cyclophosphamide and interleukin-12 (IL-12) gene therapy against advanced gastrointestinal carcinoma, in mice. Here, we assessed whether the delivery of IL-12 by gene therapy together with metronomic cyclophosphamide exerts antitumor effects in a murine model of colorectal carcinoma. This combination therapy was able, at least in part, to reverse immunosuppression, by decreasing the number of regulatory T cells (Tregs) as well as of splenic myeloid-derived suppressor cells (MDSCs). However, metronomic cyclophosphamide plus IL-12 gene therapy failed to increase the number of tumor-infiltrating T lymphocytes and, more importantly, to induce a specific antitumor immune response. With respect to this, cyclophosphamide at a single low dose displayed a superior anticancer profile than the same drug given at a metronomic schedule. Our results may have important implications in the design of new therapeutic strategies against colorectal carcinoma using cyclophosphamide in combination with immunotherapy.
authors.affiliation: Gene Therapy Laboratory; Liver Unit; School of Medicine; Austral University; Buenos Aires, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: Malvicini
authors.forename: Laura
authors.initials: L
authors.lastname: Alaniz
authors.forename: Juan
authors.initials: J
authors.lastname: Bayo
authors.forename: Mariana
authors.initials: M
authors.lastname: Garcia
authors.forename: Flavia
authors.initials: F
authors.lastname: Piccioni
authors.forename: Esteban
authors.initials: E
authors.lastname: Fiore
authors.forename: Catalina
authors.initials: C
authors.lastname: Atorrasagasti
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Aquino
authors.forename: Pablo
authors.initials: P
authors.lastname: Matar
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mazzolini