Combined chemotherapy of murine mammary tumors by local activation of the prodrugs ifosfamide and 5-fluorocytosine.
The success of chemotherapeutic intervention is limited because the necessary high local drug doses cannot be achieved without systemic toxicity. Application of suicide genes (SGs) and direct conversion of prodrugs (PDs) to toxic metabolites in situ by SGs may enhance the efficacy of chemotherapy. To evaluate this strategy in two murine breast cancer models, TS/A and GR, we injected cellulose sulfate capsules harboring cat kidney cells expressing the SGs cytosine deaminase and cytochrome P450 2B1 (CYP2B1) intratumorally. The PDs 5-fluorocytosine and ifosfamide were administered in 3-day intervals. The effect of in situ chemotherapy with each PD alone and the combination was analyzed over a period of 100 days. The results reveal that for TS/A tumors, the antitumoral effect mediated by CYP2B1 is more efficient than that of cytosine deaminase, whereas for GR tumors, both systems worked equally well. Furthermore, we find additive toxicity using both SG/PD systems for both TS/A and GR tumors.
Kammertoens
T
T
Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany. tkamm@mdc-berlin.de
Gelbmann
W
W
Karle
P
P
Alton
K
K
Saller
R
R
Salmons
B
B
Günzburg
W H
WH
Uckert
W
W
D000818:Animals; D002415:Cats; D002460:Cell Line; D017690:Cell Transplantation; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics* / Q000378:metabolism; D043525:Cytosine Deaminase; D005260:Female; D005437:Flucytosine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D007069:Ifosfamide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007668:Kidney; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009700:Nucleoside Deaminases / Q000235:genetics* / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014162:Transfection; D014407:Tumor Cells, Cultured
D011355:Prodrugs; D005437:Flucytosine; D019362:Cytochrome P-450 CYP2B1; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D007069:Ifosfamide