Chemotherapy in vivo against M109 murine lung carcinoma with cytochalasin B by localized, systemic, and liposomal administration

Abstract

Cytochalasin B is a potentially novel microfilament-directed chemotherapeutic agent that prevents actin polymerization, thereby inhibiting cytokinesis. Although cytochalasin B has been extensively studied in vitro, only limited data are available to assess its in vivo potential. Cytochalasin B was administered to Balb/c mice challenged i.d. with M109 murine lung carcinoma to determine whether the agent could affect an established i.d. tumor when the compound is administered s.c. in the region of the i.d. tumor, but not in direct contact with it. Cytochalasin B was also administered either i.p. or s.c. at a distant site or i.v. to determine whether it could affect the long-term development of an established i.d. tumor. Cytochalasin B was then liposome encapsulated to determine whether the maximum tolerated dose (MTD) of the compound could be increased, while reducing immunosuppression that we have previously characterized. Liposomal cytochalasin B was also administered to mice challenged i.d. with M109 lung carcinoma to assess its chemotherapeutic efficacy. The results can be summarized as follows: 1) cytochalasin B substantially delayed the growth of i.d. M109 tumor nodules, inhibited metastatic progression in surrounding tissues, and produced long-term cures in treated mice; 2) liposomal cytochalasin B increased the i.p. MTD by more than 3-fold, produced a different distribution in tissue concentrations, and displayed antitumor effects against M109 lung carcinoma similar to non-encapsulated cytochalasin B. These data show that cytochalasin B exploits unique chemotherapeutic mechanisms and is an effective antineoplastic agent in vivo in pre-clinical models, either in bolus form or after liposome encapsulation.

PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction

“…Although there are no microfilament-directed agents currently approved by the FDA or other pharmaceutical regulating bodies, these compounds have intriguing therapeutic potential. Antineoplastic mechanisms of these agents include the potentiation of multinucleated cancer cells that are exquisitely sensitive to other forms of chemotherapy via inhibition of cytokinesis, reducing metastatic potential by limiting cell motility and adhesion (as well as inhibiting the secretion of glucosaminidases), and binding ATPbinding cassette (ABC) transporters, thereby enhancing the activity of other chemotherapeutic agents [1,152,153]. Due to their unique mechanisms of action, microfilament-directed agents have been shown to sensitize malignant cells to mTOR inhibitors, nucleic acid-directed agents and microtubule-directed agents [154][155][156][157][158].…”

Preparation, In Vivo Administration, Dose-Limiting Toxicities, and Antineoplastic Activity of Cytochalasin B

“…Cytochalasin B was prepared in suspension form in 2% carboxymethyl cellulose 1% Tween 20 (CMC/Tw) and in solution in dimethyl sulfoxide (DMSO) and 33% ethanol:0.9% NaCl solution as previously described [17–19] . In addition, cytochalasin B was liposome encapsulated in unilamellar vesicles of egg phosphatidylcholine:dimyristoylphosphatidylglycerol using methods previously described [19] . Doxorubicin was prepared in solution using the 33% ethanol:0.9% NaCl solution.…”

“…Interestingly, cytochalasin B appears to have notable efficacy against highly metastatic cell lines, having higher in vitro cytotoxicity against cell lines selected for metastatic propensity than for the original parental cancer cell line. In addition, cytochalasin B substantially reduces the extent of metastases found in challenged mice [17–19] . These observations are in accordance to the mechanisms of cytochalasin congeners, as functioning microfilaments are essential for neoplastic cell motility, invasion, and metastasis [20–24] .…”

“…In addition to our in vitro work, we have extensively characterized the in vivo activity of cytochalasin B against solid tumors and disseminated cancers of murine origin [17–19] . Not only does cytochalasin B significantly improve the lifespan of mice challenged with lung carcinoma, melanoma, or leukemia, but long-term survival is frequently observed [17–19] . Interestingly, cytochalasin B appears to have notable efficacy against highly metastatic cell lines, having higher in vitro cytotoxicity against cell lines selected for metastatic propensity than for the original parental cancer cell line.…”

“…We also examine the routes of administration and the maximum tolerated doses (MTDs) of cytochalasin B in multiple murine models. This analysis includes cytochalasin B that has been liposome encapsulated, as we have previously shown that this formulation reduces cytochalasin B-associated immunosuppression while retaining marked antitumor activity [19] . We then extend our previous in vivo findings by examining the effects of a well-tolerated i.v.…”