FTY720 inhibits tumor growth and angiogenesis.
De novo malignancies and recurrence of tumors are some of the biggest threats to allograft recipients subjected to chronic immunosuppression. FTY720, a synthetic myriocin analogue, is an immunosuppressant that induces apoptosis of activated lymphocytes and prevents infiltration of lymphocytes into allografts, thereby prolonging allograft survival in a dose-dependent manner. Additionally, FTY720 was shown to prevent tumor growth and metastasis. Therefore, we examined the effect of FTY720 on angiogenesis in a HUVEC spheroid model. To substantiate our in vitro findings the effect of FTY720 was also tested in C57/B16 mice subcutaneously injected with Lewis Lung Carcinoma (LLC1) cells. After establishment of a palpable tumor the animals were treated daily with either saline or 1, 5, or 10 mg/kg FTY720. Subsequently, the tumor size was measured, periodically. In our experiments FTY720 showed a strong antiangiogenic effect, overcoming the stimulating effect of VEGF (20 ng/mL) even at subnanomolar concentrations. In vivo, FTY720 showed a dose-dependent inhibition of subcutaneous tumors, and the tumor size of animals treated with 10 mg/kg FTY720 was less than half of the size of tumors in control animals. In conclusion, FTY-720 demonstrated a strong antiangiogenic effect in vitro and a substantial antitumor effect in vivo. Presumably, the stabilizing effect of surrounding pericytes limits the effect of FTY720 in our mouse model. Therefore, a combination of FTY720 with an mTOR inhibitor might be the most favorable immunosuppressive drug combination for allograft recipients at risk for tumor development.
Schmid
G
G
Department of Surgery, University of Munich, Klinikum Grosshadern, Munich, Germany.
Guba
M
M
Papyan
A
A
Ischenko
I
I
Brückel
M
M
Bruns
C J
CJ
Jauch
K-W
KW
Graeb
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011409:Propylene Glycols / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives; D014471:Umbilical Veins
D000970:Antineoplastic Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine