Metronomic chemotherapy and anti‐angiogenesis: can upgraded pre‐clinical assays improve clinical trials aimed at controlling tumor growth?

Abstract

Metronomic chemotherapy, which is continuously administered systemically at close to non-toxic doses, targets the endothelial cells (ECs) that are proliferating during tumor angiogenesis. This leads to harmful effects of an even greatly increased number contiguous tumor cells. Although pre-clinical studies of angiogenesis-related EC features in vitro and of the anti-angiogenic and anti-tumor effects in vivo of metronomic chemotherapy have provided valuable insights, clinical trials with this type of therapy have been less successful in inhibiting tumor growth. One possible reason for the apparent disconnect between the pre-clinical and clinical outcomes is that most of the currently used experimental angiogenesis assays and tumor models are incapable of yielding data that can be translated readily into the clinical setting. Many of the assays used suffer from unintentional artifactual effects, e.g., oxidative stress in vitro, and inflammation in vivo, which reduces the sensitivity and discriminatory power of the assays. Co-treatment with an antioxidant or the inclusion of antioxidants in the vehicle often significantly affects the angiogenesis-modulating outcome of metronomic mono-chemotherapy in vivo. This ‘metronomic chemotherapy vehicle factor’ merits further study, as do the observations of antagonistic effects following metronomic treatment with a combination of standard chemotherapeutic drugs in vivo.

How tumor growth can be influenced by delayed interactions between cancer cells and the microenvironment?

“…According to the second lemma in [47], every solution of system (4) with the initial conditions (5), Let us now consider the first equation of system (4). From the nonnegativity of its solutions, the right-hand side of system (4) is bounded by…”

“…These algorithms were validated with many experimental times series [68,69]. Rather than imposing a priori the structure of the differential equations and only identifying parameter values, we preferred to leave a structure selection technique providing such a structure directly from the time series produced by the system (4) with two delays. As other available techniques [70,71], the structure selection here used [67] has a strong limitation since it is not possible for now to deal with rational functions as would be required for the first equation of system (4).…”

“…Cancer or malignant tumor is a world-wide problem, mainly because the underlying mechanism of tumor growth is not well understood and, consequently, is quite unpredictable and challenging to control it [1,2,3,4]. The malignant tumor invades surrounding tissues and primarily grows in the mesenchyme; it has the capability to grow in distant organs once the angiogenic switch occurred, leading to the formation of metastases.…”

“…Symbols, biological meaning and numerical values of parameters from system(4). Parameter values of the global model (58) obtained without delay (see Section 5) are also reported.…”

Metronomic oral cyclophosphamide (MOC) in the salvage therapy of heavily treated recurrent ovarian cancer patients: a retrospective, multicenter study

“…metronomic chemotherapy) has gained much attention in recent years; indeed, this route of drug administration has been shown to be as active and, in some circumstances, even more efficacious than conventionally administered chemotherapy, in spite of a negligible toxicity [ 6 – 9 ]. Antitumor activity induced by metronomic drug administration has been ascribed mainly to its anti-angiogenetic effects [ 7 – 10 ]; however, the documentation that metronomic chemotherapy activates antitumor immunity as well as tumor dormancy and senescence has established metronomic chemotherapy as a sort of multi-targeted treatment [ 11 , 12 ].…”