The effect of tirapazamine (SR-4233) alone or combined with chemotherapeutic agents on xenografted human tumours

Abstract

S_ary Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased when combined with chemotherapy drugs such as cisplatinum, depending on the timing of administration. The aim of this study was to define the toxicity (animal lethaity) and the activity (growth delay assay, excision assay) of a bioreductive drug, tirapazamine, alone and combined with chemotherapy agents (5-FU, VP16, bleo, DTIC and c-DDP) on nude mice bearing xenografted human tumours: a rectal carcinoma (HRT18) and a melanoma (Nal I +). Animal lethality was markedly increased when tirapazamine at the lethal dose 10% was combined with the other drugs. For the HRT18 tumour the combination of tirapazamine and bleomycin significantly increased the delay of regrowth compared with bleomycin alone (P=0.04) and was more cytotoxic than tirapazamine alone (P=0.04). For the Nall+ tumours the combination of tirapazamine with VP16 significantly increased tumour doubling time compared with the controls (P=0.001) or VP16 alone. The combination of tirapazamine and VP16 was more cytotoxic than VP16 alone (P=0.0001). When compared with c-DDP or tirapazamine alone, there was a significant decrease in plating efficiency when tirapazamine and c-DDP were given at the same time (P=0.04), but not when tirapazamine was given 3 h before c-DDP. In conclusion, tirapazamine was shown to be cytotoxic against clonogenic human tumour cells. Its efficacy in vivo may depend on its combination with already active chemotherapy drugs on the tumour model used. The timing of administration may be less important than previously thought.

Impact of liver P450 reductase suppression on cyclophosphamide activation, pharmacokinetics and antitumoral activity in a cytochrome P450-based cancer gene therapy model

“…The specific growth delay parameter provides an estimate of the number of doubling times by which tumor growth is delayed by drug treatment, and provides for comparisons of therapeutic responses between tumors that differ in their growth rates. 31 …”

“…Tumor growth delay data were analyzed as described previously. 31 Tumor-doubling time was defined as the time in days required for the tumor to double in surface area. Tumor growth delay values were then calculated as the difference in tumor-doubling time between the drug-treated and control groups.…”

Evaluation of the Toxicity of Tirapazamine plus Cisplatin in a Mouse Tumor Model

“…Daten der Literatur zeigen im Tierexperiment eine bis zu fünffach gesteigerte Wirkung der Kombination TPZ plus Cisplatin [10]. Zwar wird eine parallel dazu zunehmende Toxizität im Vergleich zu einer Monotherapie mit Cisplatin von diesen Autoren verneint, jedoch wurde die Toxizität der Kombinationstherapie im Mausmodell bisher nur wenig untersucht [19]. Unser Ziel war es deshalb, Nebenwirkungen und Effektivität von TPZ plus Cisplatin in Kombination mit Strahlentherapie im Mausmodell zu evaluieren und gegeneinander abzuwägen.…”

“…Insgesamt erfolgten sechs intraperitoneale Injektionen von TPZ und/oder Cisplatin (d.h. dreimal pro Woche; Abbildung 1). Die in der vorliegenden Studie verwendeten Dosierungen sind mit denen anderer Arbeitsgruppen vergleichbar[5,7,10,19]. Die LD 10 für eine alleinige Therapie mit TPZ lag in einer Arbeit von Lartigau & Guichard, bei der ein ähnliches Fraktionierungsschema verwendet wurde wie in der vorliegenden Studie, bei 140 mg/kg Körpergewicht (KG)[19].…”

Modulation of cyclophosphamide-based cytochrome P 450 gene therapy using liver P450 inhibitors

“…The specific growth delay parameter provides an estimate of the number of doubling times by which tumor growth is delayed by drug treatment, and enables comparisons of therapeutic responses between tumors that differ in their growth rates. 33 …”