Prevention of cancer recurrence in tumor margins by stopping microcirculation in the tumor and tumor-host interface.

Combretastatins interrupt blood flow of solid tumor vascular networks and lead to necrosis by blocking nutrients. However, tumors recover from tumor blood flow interruption-induced damage and develop viable rims. To investigate why cancer recurs and its prevention, we used a combretastatin derivative, Cderiv (=AC7700), and analyzed changes in tumor-host interface (T-HI) vessels, which were closest to cancer cells in the tumor margin after tumor vessel disruption, and the microenvironment surrounding them.

Starvation tactics for solid tumors: tumor blood flow interruption via a combretastatin derivative (Cderiv), and its microcirculation mechanism.

Combretastatin can prevent the supply of nutrients to cancer cells by selectively interrupting tumor blood flow (TBF). Therefore, combretastatin may serve as a new anticancer drug that utilizes starvation tactics to attack solid tumors. Among combretastatin compounds, combretastatin A-4 and a combretastatin A-4 derivative (Cderiv) are now in phase III clinical trials.

Tumor environment changed by combretastatin derivative (Cderiv) pretreatment that leads to effective tumor targeting, MRI studies, and antitumor activity of polymeric micelle carrier systems.

Purpose: To evaluate effect of a vascular disrupting agent, a combretastatin derivative (Cderiv), on tumor targeting for polymeric micelle carrier systems, containing either a diagnostic MRI contrast agent or a therapeutic anticancer drug.

Methods: Cderiv was pre-administered 72 h before polymeric micelle MRI contrast agent injection. Accumulation of the MRI contrast agent in colon 26 murine tumor was evaluated with or without pretreatment of Cderiv by ICP and MRI.

Role of peroxiredoxin III in the pathogenesis of pre-eclampsia as evidenced in mice.

As a member of peroxiredoxin (Prx) family, PrxIII has been demonstrated to play an important role in scavenging intracellular reactive oxygen species (ROS). Since PrxIII knockout mice exhibited oxidative stress in placentas resembling pathophysiologic changes in placentas of human pre-eclampsia, we measured blood pressure through the carotid artery and detected oxidative status by Western blotting in pregnant mice. We did not notice hypertension in pregnant PrxIII knockout mice as compared with wild-type littermates, although endothelin-1 was over-expressed in PrxIII-deficient placentas.

The combretastatin derivative (Cderiv), a vascular disrupting agent, enables polymeric nanomicelles to accumulate in microtumors.

A previous study found almost no leakage of polymeric nanomicelles from vessels in microtumors. If such vessels become leaky, sufficient nanomedicines may be delivered to microtumors and large tumors. To create leaky vessels, a combretastatin derivative (Cderiv), a vascular disrupting agent, was used.

Vital microscopic analysis of polymeric micelle extravasation from tumor vessels: macromolecular delivery according to tumor vascular growth stage.

Particles larger than a specific size have been thought to extravasate from tumor vessels but not from normal vessels. Therefore, various nanoparticles incorporating anticancer drugs have been developed to realize selective drug delivery to solid tumors. However, it is not yet clear whether nanoparticles extravasate readily from all tumor vessels including vessels of microtumors.

Tumor blood flow interruption after radiotherapy strongly inhibits tumor regrowth.

To clarify the therapeutic significance of interrupting tumor blood flow after irradiation, we investigated X-irradiation-induced changes in hemodynamic parameters (blood flow, extravasation and washout of fluorescein isothiocyanate-dextran, and interstitial fluid pressure) in a variant of Yoshida sarcoma, LY80. Tumors in anesthetized male Donryu rats received local irradiation (10 Gy). At 48 h after irradiation, tumor blood flow increased significantly; at 72-96 h after irradiation, a 2-2.

Antineoplastic strategy: irreversible tumor blood flow stasis induced by the combretastatin A-4 derivative AVE8062 (AC7700).

Despite extensive research efforts, effective therapies for refractive cancers have not yet been established, and development of successful treatment strategies remains the most important task in the field of oncology. We recently showed that AVE8062 (formerly AC7700), a derivative of combretastatin A-4, achieved irreversible stasis of tumor blood flow (TBF), thereby causing necrosis of tumor tissue by halting the supply of nutrients. Such effects were unrelated to cancer type.

Effect of irradiation on neovascularization in rat skinfold chambers: implications for clinical trials of low-dose radiotherapy for wet-type age-related macular degeneration.

Purpose: Wet-type age-related macular degeneration is a refractory eye disease that involves choroidal neovascularization. Randomized controlled trials of low-dose radiotherapy for this disease performed in Japan showed that, at 12 months of follow-up, visual acuity was significantly well preserved and the neovascular membrane size decreased. Because understanding the effect of irradiation on new vascular networks is an important prerequisite for clinical trials, we used a rat skinfold chamber technique to investigate X-ray-induced changes in neovasculature microcirculation.