title: Chemotherapy with cytochalasin congeners in vitro and in vivo against murine models.
abstract: Background Despite inherent differences between the cytoskeletal networks of malignant and normal cells, and the clinical antineoplastic activity of microtubule-directed agents, there has yet to be a microfilament-directed agent approved for clinical use. One of the most studied microfilament-directed agents has been cytochalasin B, a mycogenic toxin known to disrupt the formation of actin polymers. Therefore, this study sought to expand on our previous work with the microfilament-directed agent, along with other less studied cytochalasin congeners. Materials and Methods We determined whether cytochalasin B exerted significant cytotoxic effects in vitro on adherent M109 lung carcinoma and B16BL6 and B16F10 murine melanomas, or on suspension P388/ADR murine leukemia cells. We also examined whether cytochalasin B, its reduced congener 21, 22-dihydrocytochalasin B (DiHCB), or cytochalasin D could synergize with doxorubicin (ADR) against ADR-resistant P388/ADR leukemia cells, and produce significant cytotoxicity in vitro. For in vivo characterization, cytochalasins B and D were administered intraperitoneally (i.p.) to Balb/c mice challenged with drug sensitive P388-S or multidrug resistant P388/ADR leukemias. Results Cytochalasin B demonstrated higher cytotoxicity against adherent lung carcinoma and melanoma cells than against suspension P388/ADR leukemia cells, as assessed by comparative effects on cell growth, and IC₅₀ and IC₈₀ values. Isobolographic analysis indicated that both cytochalasin B and DiHCB demonstrate considerable drug synergy with ADR against ADR-resistant P388/ADR leukemia, while cytochalasin D exhibits only additivity with ADR against the same cell line. In vivo, cytochalasins B and D substantially increased the life expectancy of mice challenged with P388/S and P388/ADR leukemias, and in some cases, produced long-term survival. Conclusion Taken together, it appears that cytochalasins have unique antineoplastic activity that could potentiate a novel class of chemotherapeutic agents.
authors.affiliation: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA, mrtrendo@syr.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Trendowski
authors.forename: Joan M
authors.initials: JM
authors.lastname: Mitchell
authors.forename: Christine M
authors.initials: CM
authors.lastname: Corsette
authors.forename: Christopher
authors.initials: C
authors.lastname: Acquafondata
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Fondy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003571:Cytochalasin B / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D015638:Cytochalasin D / Q000008:administration & dosage / Q000494:pharmacology; D003572:Cytochalasins / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D007941:Leukemia P388 / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003572:Cytochalasins; D015638:Cytochalasin D; C024794:dihydrocytochalasin B; D003571:Cytochalasin B; D004317:Doxorubicin