RESUMO
Blood vessels in the tumor periphery have high pericyte coverage and are resistant to vascular disrupting agents (VDAs). VDA treatment resistance leads to a viable peripheral tumor rim that contributes to treatment failure and disease recurrence. Here, we provide evidence to support a hypothesis that shifting the target of VDAs from tumor vessel endothelial cells to pericytes disrupts tumor peripheral vessels and the viable rim, circumventing VDA treatment resistance. Through chemical engineering, we developed Z-GP-DAVLBH (from the tubulin-binding VDA desacetylvinblastine monohydrazide [DAVLBH]) as a prodrug that can be selectively activated by fibroblast activation protein α (FAPα) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAPα-expressing tumor pericytes, disrupting blood vessels both within the core and around the periphery of tumors. As a result, Z-GP-DAVLBH treatment eradicated the otherwise VDA-resistant tumor rim and led to complete regression of tumors in multiple lines of xenografts without producing the drug-related toxicity that is associated with similar doses of DAVLBH. This study demonstrates that targeting tumor pericytes with an FAPα-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments.
Assuntos
Inibidores da Angiogênese/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Pró-Fármacos/farmacologia , Vimblastina , Células A549 , Animais , Células 3T3 BALB , Endopeptidases , Gelatinases/biossíntese , Células HeLa , Células Hep G2 , Humanos , Proteínas de Membrana/biossíntese , Camundongos , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Pericitos , Serina Endopeptidases/biossíntese , Vimblastina/análogos & derivados , Vimblastina/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Two new compounds, along with two known compounds, were isolated from the barks of Parabarium huaitingii, and their structures were determined as 5α-pregn-6-ene-3ß,17α,20(S)-triol-20-O-ß-d-digitoxopyranoside (1), cymaropyranurolactone 4-O-ß-d-digitalopyranosyl-(1 â 4)-O-ß-d-cymaropyranosyl-(1 â 4)-O-ß-d-oleandropyranosyl-(1 â 4)-O-ß-d-cymaropyranoside (2), 3ß,17α,20(S)-trihydroxy-5α-pregn-6-ene (3), and 5α-pregn-6-ene-3ß,17α,20(S)-triol-3-O-ß-d-digitalopyranoside (4) by spectroscopic methods.