Antitumor activity of the angiogenesis inhibitor TNP-470 on murine lymphoma/leukemia cells in vivo and in vitro.
OBJECTIVE
The aim of this study was to evaluate the effects of an angiogenesis inhibitor in a non-immunocompromised setting in which transplanted tumor cells home and expand in a manner mimicking the original tumor in the donor. We used a novel animal model for T-cell lymphoma/leukemia (TLL) to test the antitumor effect of TNP-470, a well-established angiogenesis inhibitor.


METHODS
Cells from spontaneously arisen TLL tumors were transferred to syngenic recipients. The mice were treated with TNP-470 (30 mg/kg) or vehicle every other day for 2 weeks. Mice were sacrificed on day 15 after transfer, and body and organ weights were measured. Cell cycle and morphologic analysis was performed on cells and/or sections from selected organs. The cytotoxic effect of TNP-470 was assayed in vitro using the TLL-M and HL-60 cell lines.


RESULTS
TNP-470 treatment significantly reduced total tumor load and tumor mass in specific organs infiltrated with lymphoma/leukemia. This was associated with an increased apoptosis in these organs. We also observed side effects of TNP-470 not previously reported, such as diminished extramedullary erythropoiesis and disrupted liver morphology. In vitro TLL-M cells were resistant to cytotoxic effects of moderate doses of TNP-470.


CONCLUSIONS
TNP-470 treatment has a beneficial effect on tumor load in the TLL transfer model, most likely caused by the antiangiogenic effect of TNP-470. This is supported by the observation of increased apoptosis in infiltrated organs. The TLL transfer model is well suited for further studies of combinations with TNP-470 or other angiogenesis inhibitors and cytotoxic drugs.
Norén-Nyström
Ulrika
U
Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden.
Eriksson
Maria
M
Eriksson
Björn
B
Roos
Göran
G
Bergh
Anders
A
Holmberg
Dan
D
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003510:Cyclohexanes; D004353:Drug Evaluation, Preclinical; D004920:Erythropoiesis / Q000187:drug effects; D018922:HL-60 Cells; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D017254:Leukemic Infiltration / Q000188:drug therapy; D008099:Liver / Q000187:drug effects; D008223:Lymphoma / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D014185:Transplantation, Isogeneic; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol