In vivo apoptosis detection with radioiodinated Annexin V in LoVo tumour-bearing mice following Tipifarnib (Zarnestra, R115777) farnesyltransferase inhibitor therapy.
In this paper, the use of (123)I-Annexin V for the detection of farnesyltransferase inhibitor (FTI)-induced apoptosis in tumour-bearing athymic mice is described. In vitro binding assays on LoVo cells show time- and dosage-dependent (125)I-Annexin V binding upon treatment with Tipifarnib (Zarnestra, R115777), a selective and potent FTI. In vivo experiments using planar gamma scintigraphy on LoVo inoculated mice show a 40% increased (123)I-Annexin V uptake 8 h after a single oral administration of 100 mg/kg Tipifarnib in 20% beta-cyclodextrin in 0.1 M HCl, as well as after 3 days of twice daily treatments with the same dose. Ex vivo TUNEL assays, detecting end-stage apoptotic cells, correlate significantly with both in vitro and in vivo results. The percentage of necrosis is also increased by Tipifarnib treatment, but is too low to interfere with the (123)I-Annexin V uptake. It can be concluded that (123)I-Annexin V can be used to monitor Tipifarnib-induced apoptosis in LoVo xenograft tumours in athymic mice. Future applications might include the early prediction of FTI response and the selection of FTI-sensitive patients very shortly after treatment initiation. Subsequently, such patients would greatly benefit from a noninvasive and fast therapy evaluation.
Cornelissen
Bart
B
Laboratory of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium. bart.cornelissen@ugent.be
Lahorte
Christophe
C
Kersemans
Veerle
V
Capriotti
Gabriela
G
Bonanno
Elena
E
Signore
Alberto
A
Van de Wiele
Christophe
C
Dierckx
Rudi A
RA
Slegers
Guido
G
D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D017304:Annexin A5 / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011379:Prognosis; D015363:Quinolones / Q000008:administration & dosage*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
D017304:Annexin A5; D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D015363:Quinolones; D019275:Radiopharmaceuticals; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C402769:tipifarnib