PURPOSE: 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.
PURPOSE: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:MurineRIF-1fibrosarcomas 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.
Authors: D Rischin; L Peters; R Hicks; P Hughes; R Fisher; R Hart; M Sexton; I D'Costa; R von Roemeling Journal: J Clin Oncol Date: 2001-01-15 Impact factor: 44.544
Authors: B G Wouters; Y M Delahoussaye; J W Evans; G W Birrell; M J Dorie; J Wang; D MacDermed; R K Chiu; J M Brown Journal: Cancer Res Date: 2001-01-01 Impact factor: 12.701
Authors: M Höckel; C Knoop; K Schlenger; B Vorndran; E Baussmann; M Mitze; P G Knapstein; P Vaupel Journal: Radiother Oncol Date: 1993-01 Impact factor: 6.280
Authors: Jae-Beom Kim; Konnie Urban; Edward Cochran; Steve Lee; Angel Ang; Bradley Rice; Adam Bata; Kenneth Campbell; Richard Coffee; Alex Gorodinsky; Zhan Lu; He Zhou; Takashi Kei Kishimoto; Peter Lassota Journal: PLoS One Date: 2010-02-23 Impact factor: 3.240