Abstract
It is now well established that for tumour growth and survival, tumour vasculature is an important element. Studies have demonstrated that ultrasound-stimulated microbubble (USMB) treatment causes extensive endothelial cell death leading to tumour vascular disruption. The subsequent rapid vascular collapse translates to overall increases in tumour response to various therapies. In this study, we explored USMB involvement in the enhancement of hyperthermia (HT) treatment effects. Human prostate tumour (PC3) xenografts were grown in mice and were treated with USMB, HT, or with a combination of the two treatments. Treatment parameters consisted of ultrasound pressures of 0 to 740 kPa, the use of perfluorocarbon-filled microbubbles administered intravenously, and an HT temperature of 43°C delivered for various times (0–50 minutes). Single and multiple repeated treatments were evaluated. Tumour response was monitored 24 hours after treatments and tumour growth was monitored for up to over 30 days for a single treatment and 4 weeks for multiple treatments. Tumours exposed to USMB combined with HT exhibited enhanced cell death (p<0.05) and decreased vasculature (p<0.05) compared to untreated tumours or those treated with either USMB alone or HT alone within 24 hours. Deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and cluster of differentiation 31 (CD31) staining were used to assess cell death and vascular content, respectively. Further, tumours receiving a single combined USMB and HT treatment exhibited decreased tumour volumes (p<0.05) compared to those receiving either treatment alone when monitored over the duration of 30 days. Additionally, tumour response monitored weekly up to 4 weeks demonstrated a reduced vascular index and tumour volume, increased fibrosis and lesser number of proliferating cells with combined treatment of USMB and HT. Thus in this study, we characterize a novel therapeutic approach that combines USMB with HT to enhance treatment responses in a prostate cancer xenograft model in vivo.
Highlights
Hyperthermia (HT), known as thermal therapy, is a method used to treat cancer by increasing the target tissue temperature up to 40–45 ̊ Celsius (C) [1]
Combination treatment ultrasound-stimulated microbubble (USMB)+ HT (50 min) resulted in substantial tumour volume reduction with (103.0 ± 27.16 mm3) (p 0.05) at week 2, (135.5 ± 46.99 mm3) (p 0.05) at week 3 and (161.2 ± 6.123 mm3) at week 4 compared to pre-treatment group (212.8 ± 49.05 mm3)
The results indicated that when combined with USMB, HT treatment resulted in cell death, which increased with HT treatment duration
Summary
Hyperthermia (HT), known as thermal therapy, is a method used to treat cancer by increasing the target tissue temperature up to 40–45 ̊ Celsius (C) [1]. HT has a demonstrated ability to kill cancer cells and reduce tumour volume by destroying proteins and other components within cells [3] Studies including both biological and clinical data have revealed that HT treatment temperatures ranging from 41– 45 ̊C are effective at enhancing responses to cancer therapies including chemotherapy and radiation therapy [4] [5]. A study carried out by Pelz et al in patients with peritoneal carcinomatosis demonstrated that HT combined with chemotherapy (cisplatin, doxorubicin, mitomycin C, oxaliplatin) can paradoxically cause interference in cytotoxic effect by impacting the tumour microenvironment This resulted in a protective effect, diminishing cell death, due to the activation of several heat shock proteins (HSPs), which were overexpressed in the tumours after HT treatment [7]. Various clinical trials have been ongoing [8]
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