tirapazamine and flavone-acetic-acid

The tumour blood flow inhibitors 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and flavone-8-acetic acid (FAA) have been shown to potentiate the antitumour activity of several bioreductive drugs in vivo. Whilst the induction of hypoxia as a result of blood flow inhibition is presumed to be responsible for enhancing the activity of bioreductive drugs, no studies have examined potential interactions between DMXAA or FAA and enzymes involved in bioreductive drug activation. Both FAA and DMXAA are competitive inhibitors of the enzyme DT-diaphorase (NAD(P)H:Quinone oxidoreductase EC 1.6.99.2) with respect to NADH, with Ki values of 75 and 20 microM, respectively. Cytochromes P450 reductase and b5 reductase activities are not significantly inhibited by FAA, whereas DMXAA partially inhibits cytochrome b5 reductase activity. The cytotoxicity of the indoloquinone EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione] prop-beta-en-alpha-ol) against DLD-1 (IC50 = 0.32+/-0.08 microM) was significantly reduced when combinations of EO9 and FAA (IC50 = 12.26+/-5.43 microM) or DMXAA (IC50 > 40 microM) were used. In the case of menadione (which is detoxified by DT-diaphorase), combinations of menadione with FAA or DMXAA were more toxic (IC50 = 7.46+/-2.22 and 9.46+/-1.70 microM, respectively) than menadione alone (IC50 = 22.02+/-1.59 microM). Neither DMXAA nor FAA potentiated the activity of tirapazamine in vitro. These results suggest that the use of DMXAA and FAA to potentiate the activity of bioreductive drugs where DT-diaphorase plays a central role in either activation or detoxification may be inappropriate. The fact that FAA in particular does not inhibit other key enzymes involved in bioreductive activation suggests that it may be useful in terms of identifying DT-diaphorase-activated prodrugs.

Topics: Antineoplastic Agents; Aziridines; Cell Survival; Cytochrome Reductases; Cytochrome-B(5) Reductase; Enzyme Inhibitors; Flavonoids; Humans; Indolequinones; Indoles; NAD(P)H Dehydrogenase (Quinone); NADPH-Ferrihemoprotein Reductase; Tirapazamine; Triazines; Tumor Cells, Cultured; Vitamin K; Xanthenes; Xanthones

We have assessed the vascular effects of vinblastine and four other tubulin binding agents (dolastatin 10, dolastatin 15, combretastatin A1 and combretastatin A4), which are awaiting clinical evaluation. All five agents induce a reduction in tumour blood flow as measured by uptake of RbCI 24 h post drug administration. The degree of reduction ranged from 50% with combretastatin A1 to 90% with dolastatin 10. These reductions were similar to that seen with flavone acetic acid (FAA) and indicate that antivascular effects are a common feature of tubulin binding agents. We subsequently evaluated whether the blood flow reductions, induced by FAA and vinblastine, could be used to enhance the activity of the bioreductive drug tirapazamine. Since the kinetics and extent of blood flow reductions induced by the agents is comparable, similar therapeutic response was expected. Potentiation was only evident with FAA, indicating that this effect is not directly related to killing of hypoxic tumour cells induced as a consequence of blood flow reduction.

Topics: Animals; Antineoplastic Agents; Bibenzyls; Depsipeptides; Flavonoids; Mice; Mice, Inbred CBA; Neoplasms, Experimental; Oligopeptides; Regional Blood Flow; Stilbenes; Tirapazamine; Triazines; Tubulin; Tumor Necrosis Factor-alpha; Vinblastine

To determine whether 5,6-dimethylxanthenone acetic acid (DMXAA), a potent analogue of flavone acetic acid (FAA) inhibits blood flow in mouse mammary tumors, and to assess whether DMXAA enhances the antitumor effects of Tirapazamine (SR 4233) and the novel bioreductive drug SN 23862 (a dinitrobenbenzene mustard).. MDAH-MCa-4 mouse mammary tumors were grown i.m. in the leg of C3H/HeN mice. Tumor blood flow was assessed by the pertechnetate clearance method and subsequent growth delay was determined in the same tumors.. Administration of DMXAA (65-70 mumol/kg) resulted in inhibition of tumor blood flow to approximately 25% of control values, with no recovery observed up to 36 h post-treatment. Combination of DMXAA with SR 4233 provided a significant increase in tumor growth inhibition relative to either drug alone. In this effect, DMXAA was qualitatively similar to FAA, but was approximately 10 x more potent. The interaction between DMXAA (65 mumol/kg) and SR 4233 (200 mumol/kg) was maximal with SR 4233 given between 15 min before and 60 min after DMXAA. For SN 23862, a similar enhanced growth delay was observed in combination with DMXAA, with no obvious time dependence between 15 min before and 4 h after DMXAA. When mean values for groups treated with SR 4233 (200 mumole/kg) alone and in combination with DMXAA (65-90 mumole/kg) were compared, a correlation was observed between tumor blood flow inhibition and subsequent growth delay.. DMXAA is a potent inhibitor of blood flow in MDAH-MCa-4 tumors. Combination of this vasoactive drug with bioreductive agents leads to an enhanced antitumor effect. For SR 4233 and DMXAA, this enhanced effect may be predictable by measurement of tumor blood flow inhibition shortly after drug administration.

Topics: Aniline Mustard; Animals; Antineoplastic Agents; Drug Synergism; Female; Flavonoids; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Regional Blood Flow; Tirapazamine; Triazines; Xanthenes; Xanthones

Flavone acetic acid (FAA, NSC 347512) is a new anticancer drug currently undergoing clinical investigation. Although the precise mechanism for its broad spectrum of activity against transplanted murine solid tumors is unknown, it has been reported that FAA reduces tumor blood flow and produces hemorrhagic necrosis. We have confirmed this finding with the murine transplanted carcinoma SCCVII: 200 mg/kg FAA reduced tumor blood flow to 20-30% of normal for 1-2 days as determined by rubidium 86 extraction. In an attempt to exploit the tumor hypoxia produced by FAA, we have combined it with the novel bioreductive drug SR 4233, a benzotriazine dioxide with high selective toxicity for hypoxic cells. Marked enhancement of the antitumor effect of FAA (200 mg/kg) was observed when it was combined with SR 4233 (0.1 and 0.2 mmol/kg). This was seen using tumor cell survival, regrowth delay, and histological endpoints, with the best results obtained when the two agents were injected simultaneously. These data suggest that targeting bioreductive cytotoxic agents to tumors by producing tumor hypoxia may be a valid way of increasing the tumor cell killing of these agents.

Topics: Animals; Antineoplastic Agents; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Flavonoids; Lethal Dose 50; Mice; Mice, Inbred C3H; Neoplasms, Experimental; Oxidation-Reduction; Regional Blood Flow; Tirapazamine; Triazines