BPR0C261 is a novel orally active antitumor agent with antimitotic and anti-angiogenic activities.

BPR0C261 is a synthetic small molecule compound cytotoxic against human cancer cells and active prolonging the lifespan of leukemia mice. In the present study, we further investigated the mechanisms of its anticancer action and found that BPR0C261 inhibited microtubule polymerization through interacting with the colchicine binding sites on tubulins, disrupted microtubule arrangement and caused cell cycle arrest at G(2)/M phase in cancer cells. BPR0C261 also inhibited the clonogenic growths of cancer cells and showed cytotoxicity against human cervical cancer cells of multidrug-resistant phenotype. In addition, BPR0C261 concentration-dependently inhibited the proliferation and migration of HUVECs and disrupted the endothelial capillary-like tube formations in HUVEC and rat aorta ring cultures. Given orally, BPR0C261 inhibited angiogenesis in s.c. implanted Matrigel plugs in mice. Notably, its IC(50) values against the endothelial cell growths were approximately 10-fold lower than those against the cancer cells. It was found orally absorbable in mice and showed a good oral bioavailability (43%) in dogs. BPR0C261 permeated through the human intestinal Caco-2 cell monolayer, suggesting oral availability in humans. Orally absorbed BPR0C261 distributed readily into the s.c. xenografted tumors in nude mice in which the tumor tissue levels of BPR0C261 were found oral dose-dependent. BPR0C261 showed in vivo activities against human colorectal, gastric, and nasopharyngeal tumors in nude mice. Most interestingly, the combination of BPR0C261 plus cisplatin synergistically prolonged the lifespans of mice inoculated with murine leukemia cells. Thus, BPR0C261 is a novel orally active tubulin-binding antitumor agent with antimitotic, apoptosis-inducing, and vasculature disrupting activities.

Antiangiogenic activities and cisplatin-combined antitumor activities of BPR0L075.

BACKGROUND: Antimitotic tubulin-binding BPR0L075 is structurally analogous to the vascular-disrupting combretastatin A-4. MATERIALS AND METHODS: In vitro/in vivo models of endothelial cells cultures, Matrigel plug assay, tumor-bearing nude mice, and murine leukemia cells-inoculated mice were utilized to evaluate BPR0L075 for antiangiogenic and antitumoral activity spectra. RESULTS: BPR0L075 concentration-dependently inhibited proliferation and migration of human umbilical vein endothelial cells (HUVECs), disrupted capillary tube formations of HUVECs and rat aorta endothelial cells, and suppressed in vivo VEGF-mediated angiogenesis in Matrigel plugs in mice. Besides inhibiting the colony growth of cancer cells, BPR0L075 suppressed growth of subcutaneously-xenografted human lung, colorectal, and cervical solid tumors in nude mice. Combination treatments of BPR0L075 plus cisplatin, compared to either agent alone, demonstrated a stronger growth inhibition against the tumor xenografts in nude mice and longer lifespan in the leukemia mice. CONCLUSION: BPR0L075 is an antitumoral and antiangiogenic agent and potentiates the anticancer activity of cisplatin.