Improved efficacy of a novel anti-angiogenic drug combination (TL-118) against colorectal-cancer liver metastases; MRI monitoring in mice.
BACKGROUND
The poor prognosis of patients with colorectal-cancer liver metastases (CRLM) and the insufficiency of available treatments have raised the need for alternative curative strategies. We aimed to assess the therapeutic potential of TL-118, a new anti-angiogenic drug combination, for CRLM treatment, in a mouse model.


METHODS
The therapeutic potential of TL-118 was evaluated and compared with B20-4.1.1 (B20; anti-VEGF antibody) and rapamycin in CRLM-bearing mice. Tumour progression and the vascular changes were monitored by MRI. Additionally, mice survival, cell proliferation, apoptosis and vessel density were evaluated.


RESULTS
This study demonstrated an unequivocal advantage to TL-118 therapy by significantly prolonging survival (threefold) and reducing metastasis perfusion and vessel density (ninefold). The underlying mechanism for TL-118-treatment success was associated with hepatic perfusion attenuation resulting from reduced nitric-oxide (NO) serum levels as elucidated by using hemodynamic response imaging (HRI, a functional MRI combined with hypercapnia and hyperoxia). Further, systemic hepatic perfusion reduction during the initial treatment phase by adding NO inhibitor has proven to be essential for reaching maximal therapeutic effects for both TL-118 and B20.


CONCLUSIONS
TL-118 harbours a potential clinical benefit to CLRM patients. Moreover, the reduction of hepatic perfusion at early stages of anti-angiogenic therapies by adding NO inhibitor is crucial for achieving maximal anti-tumour effects.
Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel.
Y
Y
Edrei
E
E
Gross
N
N
Corchia
R
R
Abramovitch
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use*; D004008:Diclofenac / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D004338:Drug Combinations; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; C575718:TL-118; D004008:Diclofenac; D009569:Nitric Oxide; D012460:Sulfasalazine; D002927:Cimetidine; D003520:Cyclophosphamide