Enlargement and Multinucleation of U937 XXXX and MCF7 @entity0 Cells by Antineoplastic Agents to Enhance Sensitivity to Low Frequency Ultrasound and to DNA-directed Anticancer Agents.

@entity1 @entity632 @entity0 @entity5 @entity1283 @entity1138 @entity1311 @entity1778 @entity2389 @entity1891
BACKGROUND/AIM: Cytochalasin B is a mycogenic toxin that preferentially damages malignant cells through multiple mechanisms. The microfilament-disrupting agent inhibits cytokinesis, producing enlarged and multinucleated neoplastic cells without enlarging or producing multinucleated normal cells. In addition, cytochalasin B has been shown to induce apoptosis and to increase the mitochondrial activity of malignant cells. In spite of these pharmacological properties potentially exploitable in @entity5 chemotherapy, no cytochalasin congener or derivative and indeed no microfilament-directed agent has yet been examined in the clinic. Nevertheless, it will likely be necessary to combine microfilament-directed agents with other chemotherapeutic agents, and potentially with other anti-neoplastic modalities to amplify the mechanisms by which microfilament-directed agents inflict damage. These combinations could increase the likelihood of obtaining clinically useful activities with microfilament-directed agents and decrease the often inevitable emergence of drug resistance. Therefore, this study intends to determine appropriate chemotherapeutic agents to use concurrently with cytochalasin B and with other microfilament-directed agents. MATERIALS AND METHODS: Since cytochalasin B has shown in vitro efficacy against anchorage-independent growth, as well as against @entity5 , both U937 @entity1 @entity1778 and MCF7 @entity1 @entity0 cells were evaluated. These cell lines were assessed for their sensitivity to a comprehensive array of chemotherapeutic agents that could amplify the cytoskeletal effects of microfilament-directed agents or that could themselves be potentiated by the cellular effects of such agents. In addition, clinically-approved microtubule-directed agents, as well as clinically-active anti-neoplastic agents not specifically cytoskeletal-directed, were examined for their ability to potentiate cell enlargement, one of the hallmark features of microfilament-directed agents. Conditions for inducing @entity1283 and multinucleation of neoplastic cells with cytochalasin B were also defined. RESULTS: U937 and MCF7 cells have differing sensitivities to chemotherapeutic agents indicating that different regimens will likely be needed for various cell types in concomitant cytochalasin B-mediated chemotherapy. It was noted that microtubule-directed agents ( @entity1311 and @entity1891 ) would likely have a synergistic effect with @entity2389 as they produced a substantial enlargement in viable cells at their 50% inhibitory (IC50) values. Interestingly, @entity632 and @entity1138 also produced considerable cell enlargement, suggesting that nucleic acid-directed agents may be used to further enhance the cell-enlargement and multinucleation effects of microfilament-directed agents if appropriate sequences and concentrations can be found for the combination of agents. A subsequent publication in this series will examine the optimal combinations of chemotherapeutic agents with microfilament-directed agents in regards to drug concentrations and sequential timing. U937 cells exposed to cytochalasin B exhibited substantial cell enlargement and multinucleation that was still prevalent 8 days post-administration depending on the concentration used. CONCLUSION: Taken together, it appears that cytochalasin B has substantial synergistic potential with microtubule- and nucleic acid-directed agents.
