Evaluation of herpes simplex virus 1 thymidine kinase-mediated trapping of (131)I FIAU and prodrug activation of ganciclovir as a synergistic cancer radio/chemotherapy.
OBJECTIVE
Evaluation of selective killing of Herpes Simplex Virus 1 thymidine kinase (HSV1-tk) expressing tumors by radiolabeled (131)I-fialuridine (FIAU), and of synergy between (131)I-FIAU and Ganciclovir (GCV).


METHODS
HSV1-tk-expressing cell lines and parental cell lines were exposed to (131)I-FIAU alone, GCV alone, or combinations. Activity and concentration were varied widely, concurrent and sequential administrations tested, and dose rate effects were studied.


RESULTS
HSV1-tk-expressing cells accumulated up to 15.7-fold more (131)I-FIAU, were growth inhibited by 2 muCi/ml, or 5 muCi/ml (131)I-FIAU, and were inhibited by two log orders lower concentrations of GCV than parental cells. However, no synergy or additive effect was observed. Dose rate variations, or sequential treatment, did not alter outcome.


CONCLUSIONS
Radioisotope therapy of HSV1-tk-expressing tumor cells with (131)I-FIAU is reported for the first time. Lack of synergy between (131)I-FIAU and GCV does not warrant further investigation of combination treatment with the two agents.
Schipper
Meike L
ML
Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University, Palo Alto, CA 94305-5427, USA.
Goris
Michael L
ML
Gambhir
Sanjiv S
SS
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004307:Dose-Response Relationship, Radiation; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015870:Gene Expression; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D013937:Thymidine Kinase / Q000235:genetics
D007457:Iodine Radioisotopes; D011355:Prodrugs; D019275:Radiopharmaceuticals; D001086:Arabinofuranosyluracil; C043457:fialuridine; D013937:Thymidine Kinase; D015774:Ganciclovir