Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity.
OBJECTIVE
Tirapazamine (TPZ) reportedly enhances the tumor cell killing effect of cisplatin up to fivefold and it is an attractive drug for combination with radiotherapy. We evaluated the toxicity of a fractionated combined treatment.


METHODS
Murine RIF-1 fibrosarcomas growing on the right hind foot of C3-H mice were used. Within 2 weeks, animals were treated with six i.p. injections of TPZ (43.2-172.8 mg/kg total), and/or cisplatin (24 mg/kg total) and ten fractions of 2 Gy to the tumor. All treatments were carried out under anesthesia. Maximum follow-up was 35 days. The local tumor control was determined by calculating the tumor doubling time t (2vo). In addition to standard toxicity assessment, the major inner organs were examined histologically.


RESULTS
The administration of low TPZ doses to the cisplatin/radiotherapy treatment caused only little changes in tumor doubling time (t (2vo)) and led to a lethality rate of 15-30%. Higher TPZ doses caused an increase in t (2vo), but also a further increase in lethality and toxicity in particular to the heart, liver, kidney and stomach. Cisplatin/radiotherapy treatment without TPZ produced no severe toxicity.


CONCLUSIONS
This is a detailed study of both the acute and delayed toxicities of combined TPZ treatment in a mouse model. In our study the addition of TPZ to the cisplatin/radiotherapy treatment caused a significant increase in toxicity with only moderate effect on the tumor.
Adam
Markus
M
Radiotherapy Practice Weilheim, Weilheim, Germany. adam.markus@gmx.de
Bayer
Christine
C
Henke
Julia
J
Grosu
Anca
A
Molls
Michael
M
Nieder
Carsten
C
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D006321:Heart / Q000187:drug effects / Q000528:radiation effects; D007668:Kidney / Q000187:drug effects / Q000528:radiation effects; D008099:Liver / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008809:Mice, Inbred C3H; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D013270:Stomach / Q000187:drug effects / Q000528:radiation effects; D015996:Survival Rate; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D015431:Weight Loss
D014227:Triazines; D000077704:Tirapazamine; D002945:Cisplatin