Dimethylformamide as an enhancer of cavitation-induced cell lysis in vitro

Polar solvents, including dimethylformamide (DMF), have been investigated as anticancer drugs, but their potential usefulness is constrained by hepatotoxic side effects. The ability to enhance drug cytotoxicity with ultrasound would be valuable in creating locally intense chemotherapy while minimizing effects peripheral to the treatment site. The effects of continuous wave ultrasound (US) (985 kHz; 0.5-2.5 W/cm2) were evaluated on cultured HL-60 human promyelocytic leukemia cells alone and with a noncytotoxic DMF dose (0.11 M). The cells were insonified in a configuration that created no cell lysis without the introduction of albumin-stabilized microbubbles into the exposure chamber. When microbubbles were introduced, US with bubbles induced cell lysis, and the presence of DMF significantly increased the lysis induced by ultrasound with bubbles. The necessary presence of microbubbles for the DMF-US synergism to occur suggests that a likely mechanism is acoustic cavitation, initiated by the presence of microbubbles as nuclei. Detection of subharmonics confirmed the presence of cavitation, and cell lysis was well correlated with the subharmonic amplitude. The results show that albumin-stabilized microbubbles, similar to those currently used as US contrast agents, may provide a significant source of nuclei and improve prospects for cancer therapy using acoustic cavitation. The evidence presented supports the hypothesis that cell damage is due to a sonochemical rather than to a sonomechanical process.