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Prodrug–carboxypeptidase G2 (e.g., ZD2767P+CPG2) can realize a targeted treatment where the specific advantage is a lack of CPG2 analogues in humans, but it is limited by low efficacy. Here ultrasound was employed to enhance ZD2767P+CPG2 (i.e., ZD2767P+CPG2+US) against chemoresistant human ovarian cancer cells. The release dynamics of ZD2767D (activated drug) by CPG2 were investigated. The in vitro efficacy was explored in SKOV3 and SKOV3/DDP (cisplatin-resistant subline) cells; spectrophotometry was established to quantify ZD2767P and ZD2767D, and then intracellular pharmacokinetics were evaluated. The in vivo efficacy was validated in both subcutaneous and orthotopic tumors. With insonation, the ZD2767D concentration was increased during an early period. Insonation synergized ZD2767P+CPG2 to enhance cell death and apoptosis, and efficacies in SKOV3 and SKOV3/DDP cells were similar. Intracellular pharmacokinetics of ZD2767D were nonproportional, and insonation increased the peak level, area under the level vs time curve, and mean residence time. In subcutaneous xenografts, ZD2767P+CPG2 and ZD2767P+CPG2+US resulted in volume-inhibitory rates of 20.4% and 26.5% in SKOV3 tumors and 36.8% and 81.6% in SKOV3/DDP tumors, respectively. In the orthotopic tumor model, the survival time in group ZD2767P+CPG2 or ZD2767P+CPG2+US was prolonged compared with group control, in SKOV3 (33.0 ± 3.5 or 39.2 ± 1.8 vs 25.0 ± 1.6 days, p< 0.0001) and SKOV3/DDP (16.2 ± 4.8 or 22.3 ± 7.3 vs 8.7 ± 3.9 days, p= 0.0015) tumors. These data indicated that ZD2767P+CPG2+US was effective against resistant ovarian cancer cells.

AbstractThe aim of this study was to determine whether photodynamic therapy (PDT) alone or combined with cisplatin (DDP), can deactivate cisplatin-resistant cancer cells. Human cancer cell lines A549 and SKOV3, and chemoresistant sublines A549/DDP and SKOV3/DDP, were subjected to PDT, DDP, or PDT combined with DDP. Cell viability and apoptosis were analyzed, and then intracellular reactive oxygen species (ROS) and proteins related to apoptosis were determined. PDT caused cell death, and PDT combined with DDP led to the highest percentage of dead cells in 4 cell lines; similar results were detected in ROS; a quantification evaluation manifested that the combined effect was addition. DDP increased the percentage of apoptotic cells, and the ROS level in A549 and SKOV3 cells, which was not observed in A549/DDP and SKOV3/DDP cells. Western blot revealed an increase of caspase 3 and Bax, and a decrease of Bcl-2, demonstrating the occurrence of apoptosis. The data suggest that PDT can efficiently deactivate resistant cells and enhance the action of DDP against resistant cancer cells.

ABSTRACTIntroduction:Sonochemotherapy is a promising strategy for the treatment of cancer, however, there is limited understanding of its pharmacokinetics (PK).Area covered:The PK profile of sonochemotherapy is evaluated based on released data. Preclinical investigations suggest that the blood PK of sonochemotherapy is similar to chemotherapy when using free anticancer drugs. When using encapsulated drugs, a lower plasma level usually occurs; however, the ultrasonic release of drugs within a tumor may lead to drugs leaking into circulation, causing a rebound in the plasma drug level; a higher drug level is detected in certain healthy organs, however this depends mostly on the pharmaceutical formulation. Sonochemotherapy increases both the level and retention time of drugs in a tumor. Clinical trials of combined chemotherapy and high intensity focused ultrasound (HIFU) are evaluated from the perspective of preclinical PK: the intratumoral PK and drug interactions under insonation, and a protocol to set the interval between drug administration and insonation are lacking.Expert opinion:Insonation can alter the PK properties of chemotherapeutics, which may exacerbate the system and/or organ toxicity of anticancer drugs. Directly employing the PK parameters validated in conventional chemotherapy plays an important role in unsatisfactory clinical outcomes of chemotherapy combined with HIFU.

Chemotherapy is undertaken perioperatively to improve the efficacy of high-intensity focused ultrasound (HIFU) for solid tumors. HIFU at a sufficient intensity for tissue ablation has recently been applied for drug delivery; ultrasonic cavitation plays an important part in HIFU and drug delivery. Hematoporphyrin and microbubbles are adjuncts because they aid cavitation. The effect of HIFU (1.0 MHz; 12,999 W/cm2in continuous waves), in the presence of hematoporphyrin and/or microbubbles, on the anticancer potency of 5-fluorouracil, cisplatin, paclitaxel, mitomycin C or adriamycin, was investigated. Insonated adriamycin resulted in a lower death rate of human cancer cells HO-8910 (45.85 ± 2.65% vs 34.84 ± 1.21%, p< 0.05), which was exacerbated when employing hematoporphyrin (34.84 ± 1.21% vs 23.09 ± 7.82%, p< 0.05) or hematoporphyrin combined with microbubbles (34.84 ± 1.21% vs. 8.79 ± 3.69%, p< 0.05); the therapeutic activity was not affected when adding microbubbles alone. High-performance liquid chromatography detected a smaller peak area after subjecting adriamycin to HIFU with the use of hematoporphyrin alone or combined with microbubbles. The other drugs were not affected. Hematoporphyrin, microbubbles and adriamycin increased the throughput of hydroxyl radicals resulting from cavitation as determined by iodine and methylene blue assays. These data suggested that the anticancer activity of a drug may be decreased by HIFU exposure (particularly in the presence of hematoporphyrin and microbubbles). Cavitation produced reactive species that attacked drug molecules, thereby decreasing their antitumor potency; this process was enhanced if the drug itself generated free radicals under insonation.

The G-protein-coupled-receptor 30 (GPR30) is a new membrane estrogen receptor. The aim of the present study was to determine the correlations among GPR30, ERα, PR, C-erbB-2, p53, TNM stage, and pathologic grade in breast carcinomas. Two hundred forty-one biopsy specimens were evaluated with immunohistochemical assays, and then correlations were analyzed. Low negative correlations of GPR30 with ERα (r= −0.144, P<0.05) and PR (r= −0.214, P<0.01) were observed. Associations of GPR30 with C-erbB-2, p53, TNM stage, and pathologic grade were not confirmed. These findings indicated that GPR30 might be an independent prognostic factor in breast carcinomas.

Chemotherapy plays a very important role in cancer treatment. However, there are still some barriers in the successful use of such therapies, mainly because of the adverse side effects of the anticancer agents and due to the development of chemoresistance. This paper focuses on the use of ultrasound to enhance chemotherapy and to overcome drug resistance. The action of many anticancer agents can be improved with the use of ultrasonic exposure either in vitroor in vivo. Drug resistance can be circumvented using ultrasound alone. Furthermore, the reversal attributable to chemoresistance modifiers, such as verapamil and PSC 833, is augmented by ultrasound. Ultrasound-mediated chemosensitization is usually achieved via increasing intracellular drug accumulation, although other mechanisms are also involved. Ultrasound also can play a role in targeted chemotherapy, releasing anticancer chemicals directly and efficiently into the lesions. However, this promising modality has not been clinically adopted so far and the reasons are discussed.

This study was to investigate the effects of high intensity focused ultrasound on vascular endothelial growth factor. A B16 melanoma model was adopted in our study. Melanoma bearing mice were randomly divided into two groups: HIFU group and surgery group. While the control group was only injected with isovolumetric normal saline solution and treated as the surgery group. We detected VEGF both in tissues and sera through immunohistochemical method and ELISA respectively. Tissues were sampled pre- and at the 3rd day post-operation in HIFU group and blood samples were taken pre- and at the 1st, 3rd, and 7th day post-operation in all the groups. As a result, in the tissues, VEGF was expressed in 80% melanomas, but none was detected in the targeted area after HIFU treatment. In the sera, there was a decreasing tendency of serum-VEGF concentrations in group HIFU and surgery after operation, while that in the control group increased after operation. The levels in the HIFU group on day 1, 3, and 7 postoperatively were all lower than that in the surgery group respectively (79.16 pg/ml vs 91.59 pg/ml; 33.64 pg/ml vs 49.39 pg/ml; 30.37 pg/ml vs 46.68 pg/ml), but there wasn't any significant difference (P > 0.05). So HIFU can destroy VEGF in the targeted area and maybe have less of an effect on serum-VEGF than surgery.