Role of vascular normalization in benefit from metronomic chemotherapy

Abstract

Metronomic dosing of chemotherapy-defined as frequent administration at lower doses-has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy.thrompospondin-1 | tumor perfusion | oxygenation | immune response | drug delivery

Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats

“…This indicated that metronomic chemotherapy modulated antitumor immunity in tumor microenvironment. The similar finding from recent report also demonstrated that metronomic chemotherapy can normalize tumor vasculature to increase tumor perfusion and oxygen pressure and improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation [35]. Based on our finding, this immune-competent orthotopic HCC model can reflect the truest experimental results and mimic the clinical condition.…”

“…On the contrary, chemotherapy reduced CD44 and CD133 expression in this rat orthotopic hepatoma. A similar finding from other research indicated metronomic chemotherapy increased the killing of CSCs via improved immune response . However, celecoxib can suppress hepatic cancer stemness and activate antitumor activity to enhance chemosensitivity in liver cancer.…”

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…Certain molecularly targeted agents, such as the anti-HER2 antibody trastuzumab, and metronomic chemotherapy can also induce vascular normalization via upregulation of thrombospondin expression 28,116,117 . Moreover, endocrine therapy for hormone-dependent tumours can also reduce VEGF levels and normalize tumour vessels 118 .…”

Targeting Inflammation to Improve Tumor Drug Delivery

“…Apart from anti-angiogenic treatment, tumor perfusion and tumor vessel function can be significantly improved using metronomic chemotherapy [26], in which lower doses of the chemotherapeutic agent are administered more frequently. In fact, metronomic administration is currently being tested in clinical trials, as it was shown to be more efficacious than maximum tolerated dose treatment in preclinical studies [27].…”

“…Thus, vascular normalization restores tumor perfusion by fortifying the vessel wall and the vascular network structure, which also decreases interstitial fluid pressure due to the reduced amount of fluid leaking from the vessels. Anti-angiogenic treatments worked well in preclinical models but failed in clinical trials [24], and combinatorial approaches have been employed extensively both in preclinical and clinical studies with varying degrees of success [9,25] whereby the anti-angiogenic drug aims to normalize and not destroy the vessels and it is combined with chemotherapy to eradicate the tumor.Apart from anti-angiogenic treatment, tumor perfusion and tumor vessel function can be significantly improved using metronomic chemotherapy [26], in which lower doses of the chemotherapeutic agent are administered more frequently. In fact, metronomic administration is currently being tested in clinical trials, as it was shown to be more efficacious than maximum tolerated dose treatment in preclinical studies [27].…”