Zoledronic acid is effective against experimental malignant pleural effusion.
BACKGROUND
Aminobiphosphonates, such as zoledronic acid (ZA), exert potent indirect antitumor effects and are currently being tested against human solid tumors. The antitumor actions of aminobiphosphonates, including angiostasis, are relevant to the pathogenesis of malignant pleural effusion (MPE), but no study has addressed the efficacy of these compounds against malignant pleural disease.


OBJECTIVE
Here we hypothesized that treatment of immunocompetent mice with ZA would halt tumor progression in a mouse model of adenocarcinoma-induced MPE.


METHODS
To induce MPE in mice, Lewis lung carcinoma cells were delivered directly into the pleural space. Subsequently, animals were treated with ZA in both a prevention and a regression protocol.


RESULTS
ZA treatment resulted in significant reductions in pleural fluid accumulation and tumor dissemination, while it significantly prolonged survival. These effects of ZA were linked to enhanced apoptosis of pleural tumor cells, decreased formation of new vessels in pleural tumors, and reduced pleural vascular permeability. In addition, ZA was able to inhibit the recruitment of mononuclear cells to pleural tumors, with concomitant reductions in matrix metalloproteinase-9 release into the pleural space. Finally, ZA limited the expression of proinflammatory and angiogenic mediators, as well as the activity of small GTP proteins Ras and RhoA, in tumor cells in vivo and in vitro.


CONCLUSIONS
ZA is effective against experimental MPE, suggesting that this intervention should be considered for testing in clinical trials.
Stathopoulos
Georgios T
GT
Department of Critical Care and Pulmonary Services, Marianthi Simou and George P. Livanos Laboratory, General Hospital Evangelismos, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. gstathop@med.uoa.gr
Moschos
Charalampos
C
Loutrari
Heleni
H
Kollintza
Androniki
A
Psallidas
Ioannis
I
Karabela
Sophia
S
Magkouta
Sophia
S
Zhou
Zongmin
Z
Papiris
Spyros A
SA
Roussos
Charis
C
Kalomenidis
Ioannis
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002199:Capillary Permeability; D018827:Carcinoma, Lewis Lung / Q000150:complications; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008175:Lung Neoplasms / Q000150:complications; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D016066:Pleural Effusion, Malignant / Q000188:drug therapy* / Q000209:etiology; D010997:Pleural Neoplasms / Q000098:blood supply / Q000150:complications / Q000473:pathology; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid