Effect of Treatment Sequencing on the Tumor Response to Combined Treatment With <scp>Ultrasound‐Stimulated</scp> Microbubbles and Radiotherapy

Klein, Jonathan; Tran, William T.; Lai, Patrick F.H.; Al‐Mahrouki, Azza; Giles, Anoja; Czarnota, Gregory J.

doi:10.1002/jum.15363

Cited by 11 publications

(6 citation statements)

References 32 publications

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“…Maximum reduction in microvessel density was observed at 6 h, which coincident with the highest cell death observed at the same time point (6 h). Similarly, the hypoxia level was found to be maximum for USMB-XRT and XRT-USMB at 6 h compared to USMB-XRT and XRT-USMB, respectively, at 0 h [ 97 ]. This study looked at the effect of reversing the sequence for USMB and XRT; however, the parameters for each treatment condition were kept constant.…”

Section: Effects Of Sequencing and Treatment Parametersmentioning

confidence: 99%

Involvement of Ceramide Signalling in Radiation-Induced Tumour Vascular Effects and Vascular-Targeted Therapy

Sharma

Czarnota

2022

IJMS

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Sphingolipids are well-recognized critical components in several biological processes. Ceramides constitute a class of sphingolipid metabolites that are involved in important signal transduction pathways that play key roles in determining the fate of cells to survive or die. Ceramide accumulated in cells causes apoptosis; however, ceramide metabolized to sphingosine promotes cell survival and angiogenesis. Studies suggest that vascular-targeted therapies increase endothelial cell ceramide resulting in apoptosis that leads to tumour cure. Specifically, ultrasound-stimulated microbubbles (USMB) used as vascular disrupting agents can perturb endothelial cells, eliciting acid sphingomyelinase (ASMase) activation accompanied by ceramide release. This phenomenon results in endothelial cell death and vascular collapse and is synergistic with other antitumour treatments such as radiation. In contrast, blocking the generation of ceramide using multiple approaches, including the conversion of ceramide to sphingosine-1-phosphate (S1P), abrogates this process. The ceramide-based cell survival “rheostat” between these opposing signalling metabolites is essential in the mechanotransductive vascular targeting following USMB treatment. In this review, we aim to summarize the past and latest findings on ceramide-based vascular-targeted strategies, including novel mechanotransductive methodologies.

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Section: Effects Of Sequencing and Treatment Parametersmentioning

confidence: 99%

Involvement of Ceramide Signalling in Radiation-Induced Tumour Vascular Effects and Vascular-Targeted Therapy

Sharma

Czarnota

2022

IJMS

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“…The duration between USMB and XRT was separated by 3, 6, 12, and 24 hours. Maximum tumor response (confirmed using power Doppler imaging and immunohistochemistry) was observed when USMB and XRT were administered 6 hours apart [ 39 ]. Their data are partially in alignment with our results that confirmed 6-hour delay between USMB and XRT caused highest cell death and decreased vascular index however, in our study, a 6-hour delay didn’t improve the treatment outcome as compared to 0 hour except for 570 kPa, 0.01% (v/v) MB.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the effects of radiation and acoustically-stimulated microbubble therapy in an in vivo breast cancer model

et al. 2023

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Ultrasound-stimulated microbubbles (USMB) cause localized vascular effects and sensitize tumors to radiation therapy (XRT). We investigated acoustic parameter optimization for combining USMB and XRT. We treated breast cancer xenograft tumors with 500 kHz pulsed ultrasound at varying pressures (570 or 740 kPa), durations (1 to 10 minutes), and microbubble concentrations (0.01 to 1% (v/v)). Radiation therapy (2 Gy) was administered immediately or after a 6-hour delay. Histological staining of tumors 24 hours after treatment detected changes in cell morphology, cell death, and microvascular density. Significant cell death resulted at 570 kPa after a 1-minute exposure with 1% (v/v) microbubbles with or without XRT. However, significant microvascular disruption required higher ultrasound pressure and exposure duration greater than 5 minutes. Introducing a 6-hour delay between treatments (USMB and XRT) showed a similar tumor effect with no further improvement in response as compared to when XRT was delivered immediately after USMB.

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“…al. found no difference between USMB-XRT and XRT-USMB treatment sequences while determining a 6-h treatment separation between XRT and USMB to produce the greatest treatment effects in a PC-3 prostate-carcinoma mouse model [ 69 ]. The exploration of the therapeutic benefits of a multi-USMB treatment sequence also warrants further investigation [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Radioenhancement with the Combination of Docetaxel and Ultrasound Microbubbles: In Vivo Prostate Cancer

2023

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Using an in vitro prostate cancer model, we previously demonstrated the significant enhancement of radiotherapy (XRT) with the combined treatment of docetaxel (Taxotere; TXT) and ultrasound-microbubbles (USMB). Here, we extend these findings to an in vivo cancer model. Severe combined immune-deficient male mice were xenografted with the PC-3 prostate cancer cell line in the hind leg and treated with USMB, TXT, radiotherapy (XRT), and their combinations. The tumors were imaged with ultrasound pre-treatment and 24 h post-treatment, following which they were extracted for the histological analysis of the tumor-cell death (DN; H&E) and apoptosis (DA; TUNEL). The tumors’ growths were assessed for up to ~6 weeks and analysed using the exponential Malthusian tumor-growth model. The tumors’ doubling time (VT) was characterized as growth (positive) or shrinkage (negative). The cellular death and apoptosis increased ~5-fold with the TXT + USMB + XRT (Dn = 83% and Da = 71%) compared to the XRT alone (Dn = 16% and Da = 14%), and by ~2–3-fold with the TXT + XRT (Dn = 50% and Da = 38%) and USMB + XRT (Dn = 45% and Da = 27%) compared to the XRT. The USMB enhanced the cellular bioeffects of the TXT by ~2–5-fold with the TXT + USMB (Dn = 42% and Da = 50%), compared with the TXT alone (Dn = 19% and Da = 9%). The USMB alone caused cell death (Dn = 17% and Da = 10%) compared to the untreated control (Dn = 0.4% and Da = 0%). The histological cellular bioeffects were correlated with the changes in the ultrasound RF mid-band-fit data, which were associated with the cellular morphology. The linear regression analysis displayed a positive linear correlation between the mid-band fit and the overall cell death (R2 = 0.9164), as well as a positive linear correlation between the mid-band fit and the apoptosis (R2 = 0.8530). These results demonstrate a correlation between the histological and spectral measurements of the tissue microstructure and that cellular morphological changes can be detected by ultrasound scattering analysis. In addition, the tumor volumes from the triple-combination treatment were significantly smaller than those from the control, XRT, USMB + XRT, and TXT + XRT, from day 2 onward. The TXT + USMB + XRT-treated tumors shrank from day 2 and at each subsequent time-point measured (VT ~−6 days). The growth of the XRT-treated tumors was inhibited during the first 16 days, following which the tumors grew (VT ~9 days). The TXT + XRT and USMB + XRT groups displayed an initial decrease in tumor size (day 1–14; TXT + XRT VT ~−12 days; USMB + XRT VT ~−33 days), followed by a growth phase (day 15–37; TXT + XRT VT ~11 days; USMB + XRT VT ~22 days). The triple-combination therapy induced tumor shrinkage to a greater extent than any of the other treatments. This study demonstrates the in vivo radioenhancement potential of chemotherapy combined with therapeutic ultrasound-microbubble treatment in inducing cell death and apoptosis, as well as long-term tumor shrinkage.

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Effect of Treatment Sequencing on the Tumor Response to Combined Treatment With Ultrasound‐Stimulated Microbubbles and Radiotherapy

Cited by 11 publications

References 32 publications

Involvement of Ceramide Signalling in Radiation-Induced Tumour Vascular Effects and Vascular-Targeted Therapy

Involvement of Ceramide Signalling in Radiation-Induced Tumour Vascular Effects and Vascular-Targeted Therapy

Evaluating the effects of radiation and acoustically-stimulated microbubble therapy in an in vivo breast cancer model

Radioenhancement with the Combination of Docetaxel and Ultrasound Microbubbles: In Vivo Prostate Cancer

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