Metronomic trofosfamide inhibits progression of human lung cancer xenografts by exerting anti-angiogenic effects.
BACKGROUND
Recent studies of conventional chemotherapeutic drugs administered in metronomic therapy schedules showed remarkable inhibitory effects on tumor angiogenesis. Subsequent and prolonged tumor regression was achieved moreover by circumventing acquired drug resistance. In this study, metronomic and conventional trofosfamide were compared on human NSCLC xenograft "LX-1."


METHODS
In vitro cytotoxicity of trofosfamide on tumor and human umbilical cord endothelial cells was determined under normoxic and hypoxic conditions. Additionally fractions and duration of cell cycles were analyzed by flow cytometry. In vivo LX-1 xenotransplanted nude mice were treated with trofosfamide in conventional and metronomic schedules (i.p./p.o.). Tumor sections were evaluated for microvessel density (MVD), relative growth fraction and apoptosis.


RESULTS
In contrast to the rapid growth of conventionally treated lung cancer, long lasting tumor growth retardation over the total treatment period was achieved with metronomic treatment. While growth fraction and apoptotic rate of LX-1 cells remained unchanged, the MVD was significantly reduced (50%).


CONCLUSIONS
Our results show advantages of a metronomic trofosfamide schedule compared to a conventional bolus therapy mainly due to inhibition of angiogenesis. In vitro data show that this mechanism works under normoxic and hypoxic conditions and suggest that this is in part a direct cytotoxic effect on endothelial cells.
Klink
T
T
Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, 23538, Lubeck, Germany.
Bela
C
C
Stoelting
S
S
Peters
S O
SO
Broll
R
R
Wagner
T
T
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D013997:Time Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; C003726:trofosfamide