The interaction between a drug and ultrasound in sonochemotherapy against ovarian cancers

Sonochemotherapy is a promising modality for cancers, but the interaction between an anticancer agent and insonation has not been understood. The interactions in vitro and in vivo were quantified in this study.

The combination index (CI) and dose reduction index (DRI) were calculated, thus determining the interaction. Human ovarian cancer cells 3AO, SKOV(3), SKOV(3) /ADR, HO-8910 and HO-8910PM were subjected to a drug or sonochemotherapy (a drug followed by nonlethal insonation but in 3AO cells). SKOV(3) /ADR was an adriamycin-resistant subclone and HO-8910PM was the subline with highly metastatic potential. Adriamycin was used for 3AO, SKOV(3) and SKOV(3) /ADR cells, and cisplatin or paclitaxel employed for HO-8910 and HO-8910PM cells. Effect of the sequence of administration of a drug and insonation on the interaction was investigated in 3AO cells.

A drug followed by ultrasound led to better anticancer effects and higher CI and DRI at each concentration compared with the alternate sequence. Sonochemotherapy resulted in a higher cell-death rate, compared with a drug alone. CIs were > 1.15 in 3AO, SKOV(3) /ADR and HO-8910 cells showing synergisms, and the value in SKOV(3) indicated an addition. In HO-8910PM cells, CI was above 1.15 at ≥ 2.0 µg/ml cisplatin or ≥ 18 µg/ml paclitaxel, and the interaction shifted from a slight antagonism, an addition to a synergism when increasing the level of cisplatin. A noticeable event in HO-8910PM cells was that a slight antagonism occurred but with a higher cell-death rate. DRIs were > 1 in all cells, indicating that the use of ultrasound reduced the required dose of a drug thus decreasing toxicities. In vivo trials resulted in a CI of 1.17 for SKOV(3) tumors and a value of 1.51 for SKOV(3) /ADR ones.

Sonochemotherapy was effective against cancers including chemoresistant and metastatic lesions, via a synergy and/or an addition. The interaction depended on both the anticancer drug and cell type. For a specific cell type and a specific drug, modulating the dose resulted in a shift of the interaction.