Evaluation of (E)-2'-deoxy-2'-(fluoromethylene)cytidine on the 9L rat brain tumor model using MRI.
(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), was evaluated as a potential treatment for malignant gliomas using the rat 9L brain tumor model. FMdC was shown to be an effective inhibitor of cell proliferation in cultured 9L cells with an EC(50) of 40 ng/ml. In vitro studies also revealed that this compound significantly inhibited incorporation of [(3)H]thymidine in 9L cells. In vivo therapeutic efficacy of FMdC was evaluated in rats harboring intracerebral 9L tumors which were treated daily with 15 mg/kg, i.p. Treatment response was quantified from changes in tumor growth rates as assessed from sequential magnetic resonance imaging (MRI) tumor volume measurements. In vivo tumor cell kill in individual animals was calculated by fitting tumor volume data with an iterative computer routine. It was estimated that therapeutically responsive rats treated with FMdC daily produced a >/= 0.1 log kill per therapeutic dose which resulted in a significant reduction in tumor growth rate. In addition, localized (1)H-MRS of intracerebral 9L tumors revealed changes in metabolite levels which correlated with therapeutic response. These results provide evidence supporting the use of FMdC in clinical trials for the treatment of malignant gliomas and reveals that MR can play an important role in the pre-clinical evaluation of novel compounds using orthotopic tumor models.
Department of Radiology, Center for Molecular Imaging, University of Michigan, Ann Arbor, MI 48109, USA. bdross@umich.edu
Brian D
BD
Ross
Thomas L
TL
Chenevert
Michael
M
Garwood
Boklye
B
Kim
Lauren D
LD
Stegman
Oded
O
Ben-Yoseph
John
J
Zwolshen
Alnawaz
A
Rehemtulla
Prasad S
PS
Sunkara
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005910:Glioma / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021621:Imaging, Three-Dimensional / Q000379:methods*; D007274:Injections, Intraperitoneal; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009368:Neoplasm Transplantation; D011522:Protons; D051381:Rats; D011916:Rats, Inbred F344; D013936:Thymidine / Q000493:pharmacokinetics; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011522:Protons; D003841:Deoxycytidine; C086432:tezacitabine; D013936:Thymidine