Effect of bevacizumab treatment on p-boronophenylalanine distribution in murine tumor

Abstract

Previous studies have demonstrated that angiogenesis inhibitors can enhance tumor inhibitory effects of chemo- and radiotherapy via their action on tumor vessels. Here, we studied the effect of the angiogenesis inhibitor, bevacizumab (Avastin), on boron distribution in a murine tumor model. The human head and neck squamous cell carcinoma cell line was used for inoculation into mice. Boron-10 concentrations in tissues were measured by prompt γ-ray spectrometry (PGA). Hoechst 33342 perfusion and p-boronophenylalanine (BPA) distribution were determined by immunofluorescence staining. Our results revealed enhanced tumor blood perfusion and BPA accumulation in tumors after Avastin treatment, suggesting that combination of angiogenesis inhibition with treatment with boron compound administration may improve the efficacy of boron neutron capture therapy (BNCT) by modifying tumor vessels. In addition, our results also demonstrated the usefulness of immunofluorescence staining for investigating boron compound distribution at the cellular level.

Non‐invasive estimation of 10B‐4‐borono‐L‐phenylalanine‐derived boron concentration in tumors by PET using 4‐borono‐2‐18F‐fluoro‐phenylalanine

“…In previous animal studies, BPA has been intraperitoneally administered due to the ease of the experimental procedure. [23][24][25][26][27] However, the pattern of increase in the blood remains unknown, and it is difficult to control blood concentration by intraperitoneal injection.…”

“…In our PET analysis, CIV of 18 F‐FBPA also showed a continuous increase of uptake in the heart, suggesting an increase in the blood concentration of 18 F‐FBPA. In previous animal studies, BPA has been intraperitoneally administered due to the ease of the experimental procedure . However, the pattern of increase in the blood remains unknown, and it is difficult to control blood concentration by intraperitoneal injection.…”

Combination therapy in cancer: effects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics

“…Results are discordant in terms of drug delivery to the tumor: some studies show increased uptake after antiangiogenic therapy [ 20 , 34 , 67 – 71 ], but others report reduced drug delivery [ 72 – 77 ]. Enhanced tumor uptake of chemotherapeutics was concomitant in some instances with improvement of vessel functionality [ 68 , 78 ], whereas in other cases there was worsening of perfusion/permeability [ 34 , 69 ]. Inefficient drug delivery was often associated with the reduction of tumor perfusion or vessel permeability.…”

“…Some studies clearly illustrate the importance of the treatment schedule, showing the temporary time window in which the antiangiogenic agent exerts beneficial effects on drug pharmacokinetics. In fact, drug penetration in tumors was enhanced only when the chemotherapeutic agent was administered within a narrow interval after anti-VEGF therapy (i.e., bevacizumab) [ 20 , 67 , 68 ].…”

How to schedule VEGF and PD-1 inhibitors in combination cancer therapy?

“…In combination with chemotherapy anti-VEGF improves anti-cancer therapy, although the outcome depends on the cancer type and on the scheduling of the treatment [ 2 ]. The scheduling issue arises from the fact that anti-VEGF decreases perfusion of chemotoxic agents in some cancers, including melanoma [ 3 ], breast cancer [ 4 , 5 ] and ovarian cancer [ 6 ], while it increases perfusion of chemotoxic agents in other cancers, such as colon cancer [ 7 , 8 ] and head and neck cancer [ 9 ]. More recently Asrid et al [ 10 ] reported a rapid decrease in the delivery of chemotherapy to the tumor in patients of non-small cell lung cancer (NSCLC) after anti-VEGF therapy, highlighting the importance of drug scheduling in combination therapy when anti-VEGF is one of the drugs.…”