[Evaluation of the toxicity of tirapazamine plus cisplatin in a mouse tumor model].
OBJECTIVE
Tirapazamine (TPZ) is an anticancer drug that is selectively activated by the low oxygen environment in solid tumors. Furthermore, TPZ also enhances the tumor cell-killing effect of cisplatin. So far, detailed information on the toxicity of combined treatment is rare. The authors evaluated the toxicity of TPZ in combination with cisplatin in a mouse tumor model. For this purpose, general toxicity was monitored and all inner organs were examined histologically.


METHODS
RIF-1 fibrosarcomas of murine origin growing in the right hindfoot dorsum of C3H mice were used. The animals were treated with 10 x 2 Gy irradiation plus six i.p. injections of 4 mg/kg cisplatin (total dose 24 mg/kg) together with varying doses of TPZ (0-28 mg/kg per injection; total dose 0, 43.2, 86.4, 129.6, 151.2, 172.8 mg/kg). Treatment was applied within 2 weeks (Figure 1). Total observation period was up to 35 days.


RESULTS
Combined treatment with TPZ led to a dose-dependent, significant decrease in motor activity (Table 1) and body weight and an increase in mortality (Figures 2 and 3, Tables 2 and 3). Histological analyses showed areas of necrosis in the heart, liver and kidney and gastric ulcers (Table 4). Cisplatin alone produced no severe toxicity. Tumor doubling times were TPZ dose-dependent and comparable with data from the literature (Figures 4 and 5, Table 3).


CONCLUSIONS
Unlike most data from the literature a dose-dependent increase in toxicity was seen when adding TPZ to a standard treatment of cisplatin plus irradiation. To the authors' knowledge this is the first study histologically examining in detail the organ toxicity of TPZ in a mouse model. Furthermore, they expand the rare data on long-term toxicity after TPZ plus cisplatin in a fractionated therapy regimen. The results question the usefulness of frequently performed therapeutic studies where only short-term treatment and observation endpoints are used, since essential toxicities are likely to be overlooked.
Adam
Markus
M
Praxis für Strahlentherapie und Radioonkologie, Röntgenstrasse 4, 82362 Weilheim. markus.adam@strahlentherapie-weilheim.de
Ottenjann
Sigrid
S
Künzel
Georg
G
Busch
Raymonde
R
Erhardt
Wolf
W
Nieder
Carsten
C
Molls
Michael
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity*; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D003131:Combined Modality Therapy; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008809:Mice, Inbred C3H; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000633:toxicity*; D011879:Radiotherapy Dosage; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D013997:Time Factors; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage / Q000633:toxicity*
D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D002945:Cisplatin