Antiangiogenic effect of metronomic paclitaxel treatment in prostate cancer and non‐tumor tissue in the same animals: a quantitative study

Abstract

Well-tolerated continuous or metronomic chemotherapy can exert a marked antiangiogenic and thus superior antitumor effect compared with conventional high-dose, temporarily spaced-out chemotherapy, as shown in preclinical studies. There is, however, no means of directly assessing the antiangiogenic effect in a tumor, a serious impediment to assessing the effects of putative antiangiogenic chemotherapeutics or treatments. In an attempt to circumvent or minimize this impediment we studied the antiangiogenic effect of well-tolerated metronomic paclitaxel therapy in a surrogate tumor-free tissue that allows true quantitative analysis as well as in syngeneic At-1 prostate cancer in the same rat. This novel model allows an accurate comparison of the angiogenesis-modulating effect of chemotherapy in the two tissues to be made. The effect of chemotherapy on VEGF-A-mediated angiogenesis, a characteristic of most tumors, was assessed truly quantitatively by microscopic morphometry and image analysis in the tumor-free mesentery. The chemotherapy significantly suppressed VEGF-A-mediated angiogenesis in the mesentery to an extent that closely mirrored the significant increase in tumor necrosis measured morphometrically and the significant decrease in tumor growth rate. This finding opens an avenue to study quantitatively and systematically the antiangiogenic effect of chemotherapeutic modalities and treatments that approximately mirror their antiangiogenic effect in the At-1 tumor.

On metronomic chemotherapy: Modulation of angiogenesis mediated by VEGE-A

“…We performed a dose-finding experiment with each agent using continuous infusion for seven consecutive days, continuous infusion being the extreme of metronomic scheduling. The doses were based on data in the literature and our own findings in previous experiments [14,15]. The intention was to find doses that would diminish the weight by at most 10 Á/15% at sacrifice, as compared with the rapidly growing vehicle control animals.…”

“…The assay that was used here permits the true quantitative assessment of a variety of objective angiogenesis variables and robust statistical analysis [20Á/22]. It is noteworthy that this model closely mirrors the directly recorded growth-retarding and indirectly assessed antiangiogenic effect of metronomic chemotherapy in a syngeneic rat cancer model [15]. We believe that an approach of this kind, that permits the detailed assessment of the doserelated angiogenesis-modulating effects per se of chemotherapeutic agents, may be a useful and perhaps necessary complement to preclinical studies in tumor models.…”

Dose effects of continuous vinblastine chemotherapy on mammalian angiogenesis mediated by VEGF-A

“…It is also important to consider the fact that multiple proangiogenic factors can be expected to operate in advanced cancers [25]. The present assay of VEGF-A-mediated angiogenesis has, however, been shown closely to reflect the indirectly assessed antiangiogenic and actual growth-retarding effect of metronomic chemotherapy in a syngeneic rat prostate cancer model [29].…”

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

“…It has attracted attention given that it may reduce the risk of developing drug resistance while reducing the toxic effects. 41 One of the main antitumor mechanisms of LDM is the antiangiogenic activity, since endothelial precursor cells are more sensitive to cytotoxic drugs than tumor cells themselves. 42,43 Such effect was shown to be enhanced in vivo by combination with antiangiogenic agents.…”

“…This drug overcomes the angiogenic role of VEGF-A and reduces the rate of prostate cancer growth in rats by 24% and the vascularized area by 35%. 41 However, the benefits of LDM and antiangiogenic therapies are generally limited by acquired resistance 76 ; since, these regimens might lead to selection of hypoxia-resistant tumor cell populations as a mechanism of tumor escape. 77 In addition, patients under LDM PTX show less pronounced side effects such as body weight loss and leukopenia than those treated with MTD.…”