The Proper Administration Sequence of Radiotherapy and Anti-Vascular Agent—DMXAA Is Essential to Inhibit the Growth of Melanoma Tumors

Abstract

Vascular disrupting agents (VDAs), such as DMXAA, effectively destroy tumor blood vessels and cause the formation of large areas of necrosis in the central parts of the tumors. However, the use of VDAs is associated with hypoxia activation and residues of rim cells on the edge of the tumor that are responsible for tumor regrowth. The aim of the study was to combine DMXAA with radiotherapy (brachytherapy) and find the appropriate administration sequence to obtain the maximum synergistic therapeutic effect. We show that the combination in which tumors were irradiated prior to VDAs administration is more effective in murine melanoma growth inhibition than in either of the agents individually or in reverse combination. For the first time, the significance of immune cells’ activation in such a combination is demonstrated. The inhibition of tumor growth is linked to the reduction of tumor blood vessels, the increased infiltration of CD8+ cytotoxic T lymphocytes and NK cells and the polarization of macrophages to the cytotoxic M1 phenotype. The reverse combination of therapeutic agents showed no therapeutic effect and even abolished the effect of DMXAA. The combination of brachytherapy and vascular disrupting agent effectively inhibits the growth of melanoma tumors but requires careful planning of the sequence of administration of the agents.

3D-Cultured Vascular-Like Networks Enable Validation of Vascular Disruption Properties of Drugs In Vitro

“…Flavonoids such as 5,6-dimethyl-9-oxo-9H-xanthene-4-acetic acid (DMXAA) as potent cytokine inducers or tubulin-binding agents such as combretastatin A4 with its water-soluble prodrug combretastatin A4 disodium phosphate (CA4P) are prominent representatives of VDAs ( Hinnen and Eskens, 2007 ; Porcù et al, 2014 ). Both drug types increase the permeability of the tumor vasculature resulting in blood leakage, uncontrolled blood coagulation, rapid shutdown of the tumor core from blood supply, and subsequent tumor tissue necrosis ( Nagaiah and Remick, 2010 ; Drzyzga et al, 2021 ; LINCS, 2022 ; PubChem, 2022 ). In clinical trials, a variety of carcinomas have indeed been effectively treated with such antiangiogenic drugs and/or VDAs.…”

“…However, cancerous cells in the carcinoma rim often survive the VDA treatment and quickly repopulate the tumor. Therefore, simultaneous application of vascular-targeting agents with conventional cytotoxic anticancer therapeutics or sequential combination with radiotherapy to curb tumor proliferation is encountered a promising strategy in the treatment of solid tumors ( Siemann and Horsman, 2009 ; Drzyzga et al, 2021 ). Current challenges of VDAs in single and combination therapies are adverse effects such as cardiovascular toxicity observed in preclinical and clinical studies, which manifests as cardiac ischemia, hypertension, or atrial fibrillation and requires the establishment of meticulous clinical management protocols ( Gill et al, 2019 ).…”

Biomaterials-Mediated Tumor Infarction Therapy

“…Drzyzga et al combined vascular infarction therapy and radiotherapy to explore the best delivery conditions to improve treatment ( Drzyzga et al, 2021 ). Thrombin and chemotherapy drug doxorubicin (Dox) have also been integrated into a single nanocarrier to enable chemotherapy and blood coagulation to work together.…”

“…Drzyzga et al combined DMXAA (5,6-dimethylxanthenone-4-acetic acid) with radiotherapy to suppress tumor cells and the effect of the treatment ( Drzyzga et al, 2021 ) ( Anselmo et al, 2014 ). DMXAA was used to destroy vascular endothelial cells of the tumor to expose collagen and activate platelets, which aggregated into clumps to form thrombus through positive feedback.…”

“…In this circumstance, the idea of combined therapy based on biomaterials and infarction agents offers promise to inhibit tumor progression ( Zheng et al, 2020 ; Zhao D. et al, 2021 ; Chen et al, 2021 ). First, currently available biomaterials (such as peptides, nanorobots, and antibodies) functionalize therapeutic drugs, thus enabling the agent to precisely target endothelial cells of the tumor, improve the safety of the drug, and enhance its anti-tumor effects ( Seidi et al, 2018 ; Li et al, 2020 ; Zhao Y. et al, 2021 ; Drzyzga et al, 2021 ). Second, biomaterials are used as carriers to simultaneously carry multiple therapeutic agents for combined treatment to damage tumor cells in a multi-dimensional and comprehensive manner ( Colli et al, 2017 ; Wei et al, 2021 ; Zheng and Ding, 2022 ).…”