We studied a combination of photodynamic therapy (PDT) and sonodynamic therapy (SDT) for improving tumoricidal effects in a transplantable mouse squamous cell carcinoma (SCC) model. Two sensitizers were utilized: the pheophorbide-a derivative PH-1126, which is a newly developed photosensitizer, and the gallium porphyrin analogue ATX-70, a commonly used sonosensitizer. Mice were injected with either PH-1126 or ATX-70 i.p. at doses of 5 or 10 mg/kg.bw. At 24 (ATX-70) or 36 hr (PH-1126) (time of optimum drug concentration in the tumor) after injection, SCCs underwent laser light irradiation (88 J/cm2 of 575 nm for ATX-70; 44J/cm2 of 650 nm for PH-1126) (PDT), ultrasound irradiation (0.51 W/cm2 at 1.0 MHz for 10 minutes) (SDT), or a combination of the two treatments. The combination of PDT and SDT using either PH-1126 or ATX-70 as a sensitizer resulted in significantly improved inhibition of tumor growth (92-98%) (additive effect) as compared to either single treatment (27-77%). The combination using PH-1126 resulted in 25% of the treated mice being tumor free at 20 days after treatment. Moreover, the median survival period (from irradiation to death) of PDT + SDT-treated mice (> 120 days) was significantly greater than that in single treatment groups (77-95 days). Histological changes revealed that combination therapy could induce tumor necrosis 2-3 times as deep as in either of the single modalities. The combination of PDT and SDT could be very useful for treatment of non-superficial or nodular tumors.

The advances in preclinical cancer models, including orthotopic implantation models or genetically engineered mouse models of cancer, enable pursuing the molecular mechanism of cancer disease that might mimic genetic and biological processes in humans. Lung cancer is the major cause of cancer deaths; therefore, the treatment and prevention of lung cancer are expected to be improved by a better understanding of the complex mechanism of disease. In this study, we have examined the quantification of two distinct mouse lung cancer models by utilizing imaging modalities for monitoring tumor progression and drug efficacy evaluation. The utility of microcomputed tomography (micro-CT) for real-time/non-invasive monitoring of lung cancer progression has been confirmed by combining bioluminescent imaging and histopathological analyses. (1) therefore, the treatment and prevention of lung cancer are major unmet needs that could be improved by a better understanding of the molecular process and progression of the disease. Advances in preclinical cancer models including orthotopic implantation models or genetically engineered mouse models (GEMMs) of cancer enable investigation of the molecular mechanism of cancer disease that might better mimic genetic and biological processes in humans than the conventional subcutaneous transplant model. (2,3) It has been recently appreciated that the tumor microenvironment plays an important role for cancer cell survival, progression, and acquiring malignant metastatic ability.(2,3) Orthotopic tumor implantation models have been considered to reflect the tumor microenvironment; therefore, tumor cells often resemble clinical cancer disease processes.(4) Amongst various cancer GEMMs that have developed to resemble human cancer disease, transgenic expression of an oncogenic mutant K-ras G12D gene in mouse lung tissues has been known to result in the development of lung adenocarcinoma, (5) and further additional expression of p53 R270H dominant-negative mutant gene using the Cre-lox recombinase has been shown to promote K-ras G12D -initiated lung cancer development.(6) Despite these advances in preclinical cancer model development, their application to the drug discovery process has often been challenging because of the difficulties in assessing quantitative information for efficacy evaluations of new drug candidates. (2,3,7,8) Imaging technology has been playing a larger role for in vivo real-time/non-invasive monitoring of disease progression as well as evaluation of the efficacy of therapeutic approaches in preclinical animal models.(9) Bioluminescence imaging (BLI) takes advantage of the detection of photons emitted by luciferaseexpressing cells in the living animal and has been used for quantitative monitoring of tumor growth or disseminated matastatic disease in deeper tissue with high sensitivity.(10-14) Amongst clinical imaging modalities, X-ray computed tomography (CT) has been demonstrated as a quantitative tool for detecting lung cancer in clinical settings and also in preclinical an...

No abstract

Acoustic cavitation, the primary mechanism of sonochemical effects, is known to be induced more easily by standing waves than by progressive waves. It has been found that acoustic cavitation can be an order of magnitude enhanced by superimposing the second harmonic on the fundamental. Significant synergistic effects between the fundamental and the second harmonic were observed in both in vitro and in vivo experiments employing a progressive wave field. Second-harmonic superimposition induces in vitro sonochemical reaction as well as fractional harmonic emission at a relatively low ultrasonic intensity even in a progressive wave field. The effect of second-harmonic superimposition was also investigated using exteriorized mouse livers suspended in degassed saline. The intensity threshold for the production of focal tissue damage, paired with fractional harmonic emission was significantly lowered by second-harmonic superimposition especially when a sonodynamically active agent had been administered to the mouse. Insonation with second-harmonic superimposition in combination with such administration may have potential use for selective tumor treatment.