18[F]FDG small animal PET study of sorafenib efficacy in lymphoma preclinical models.
OBJECTIVE
Kinase inhibitors have been proposed as novel therapeutic agents in different forms of solid tumours. The Food and Drug Administration (FDA) approved the use of Sorafenib, an oral multikinase inhibitor, for advanced renal carcinoma and unresectable hepatocellular carcinoma. On-going studies are investigating the efficacy of Sorafenib in other solid tumours such as melanoma and non-small cells lung carcinoma and pre-clinical models showed the efficacy of treatment with Sorafenib in murine models of renal cells carcinoma, breast cancer, colon carcinoma and melanoma. To our knowledge, Sorafenib has never been employed in human lymphoma. The aim of the present study was to assess the efficacy of Sorafenib in murine models of human anaplastic large cells lymphoma (ALCL) and Hodgkin lymphoma (HD).


METHODS
Sorafenib cytotoxicity was assessed in vitro and growth inhibition (IC50) was calculated. Cells were assayed for Caspase-3 to measure apoptosis. Human ALCL and HD xenografts in NOD/SCID mice were monitored by small animal positron emission tomography (PET) and computed tomography (CT) over time. Tumour bearing animals were randomly selected to receive treatment with Sorafenib or no treatment. Pathology was available in all cases.


RESULTS
Sorafenib efficacy on cells proliferation and apoptosis (IC50: HD=0.0343 mg/L; ALCL=0.319 mg/L) was confirmed in vitro. Caspase-3 production showed a dose-dependent trend reaching significantly higher values for 0.046 mg/L and 0.465 mg/L drug concentrations in both cell lines. In vivo experiments showed a progressive increase of tumour lesions metabolism and dimensions regardless treatment.


CONCLUSIONS
Sorafenib showed a good cytotoxic effect in vitro especially on human HD cell line, but these findings were not confirmed in vivo. The strong discrepancy between in vitro and in vivo results suggests that further studies are needed to better acknowledge the biodistribution and metabolism of Sorafenib in NOD/SCID mice. Factors influencing drug availability at tumour site or differences in the downstream pathways may be responsible for the scarse effect of treatment.
Ambrosini
V
V
Department of Nuclear Medicine, Policlinico S. Orsola-Malpighi, Bologna University Hospital, Bologna, Italy.
Quarta
C
C
Zinzani
P L
PL
Nanni
C
C
Fini
M
M
Torricelli
P
P
Giavaresi
G
G
D'Errico-Grigioni
A
A
Malvi
D
D
Franchi
R
R
Fanti
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000662:veterinary; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008223:Lymphoma / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D049268:Positron-Emission Tomography / Q000662:veterinary*; D011379:Prognosis; D011725:Pyridines / Q000627:therapeutic use*; D019275:Radiopharmaceuticals; D000077157:Sorafenib; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D009536:Niacinamide; D000077157:Sorafenib