Enhancement of bioreductive drug toxicity in murine tumours by inhibition of the activity of nitric oxide synthase

Abstract

Summary Nitro-L-arginine inhibits the production of nitric oxide and can thereby cause vasoconstriction in vivo. One consequence of this is that nitro-L-arginine can increase hypoxia in a range of transplantable and spontaneous murine solid tumours. Bioreductive drugs such as RB6145 are more active under hypoxic conditions, and the combination of RB6145 with nitro-L-arginine in vivo shows greater anti-tumour activity than either agent individually. In mice given nitro-L-arginine at 10 mg kg-' i.p. up to 1 h before or after 300 mg kg-' i.p. RB6145, survival of KHT tumour cells was reduced by 3-4 logs when assessed by clonogenic assay 24 h after treatment. RB6145 or nitro-L-arginine alone caused no more than 20% cell kill. Similar effects were found in SCCVII tumours. The tumour response to the drug combination was tumour size dependent, with increased tumour cell sensitivity occurring when the tumour volume at the time of treatment was increased. Further, the response of KHT tumours to the combination of RB6145 and nitro-L-arginine was also dependent on the time interval between treatment and on when tumours were excised for determination of survival in vitro. The relative surviving fraction was about 0.3 for intervals less than 4 h but was reduced to 0.01 at 12 h and 0.001 at 24 h. These results were supported by histological examination of tumours, when necrosis at 2 h after treatment was less than 5% but increased to greater than 90% at 24 h. RB6145-induced normal tissue damage, as measured by CFU-A survival, was not altered by combining with nitro-L-arginine. Hence, this drug combination may provide therapeutic benefit. It is likely that the substantial anti-tumour effects are due to enhancement of bioreductive toxicity through increased tumour hypoxia, although additional mechanism(s) may also contribute to the overall response.

Targeting the Tumour Vasculature: Exploitation of Low Oxygenation and Sensitivity to NOS Inhibition by Treatment with a Hypoxic Cytotoxin

“…There are some unexplained data that suggest this effect has occurred in other laboratories. Clonogenic survival studies of hypoxic cytotoxin RB6145 in combination with NOS inhibitor L-NNA found several magnitudes greater cell kill than expected for a hypoxic cytotoxic effect when tumours were excised at 24 h [36], [41]. We propose that a large, irreversible vascular damaging effect by RB6145 combined with NOS inhibition may explain these results.…”

Electron Transfer and Oxidative Stress as Key Factors in the Design of Drugs Selectively Active in Hypoxia.

“…Nitric oxide synthases can also act as reductases of quinones [85] and other bioreductive drugs, including tirapazamine [86]. (Paradoxically, inhibition of nitric oxide synthase enhanced bioreductive drug toxicity in murine tumours [87], possibly in part through decreasing blood flow and thus inducing hypoxia.) are thermodynamically favourable (i.e.…”

Pentoxifylline improves the oxygenation and radiation response of BA1112 rat rhabdomyosarcomas and EMT6 mouse mammary carcinomas

“…Hypoxic tumor cells can be up to 3 times more resistant to radiation than their oxic counterparts [1]. Attempts to improve the efficacy of radiotherapy and chemotherapy by modifying tumor oxygenation has been an area of active research for many years [2–5]. Indeed, as early as 1930 Fischer‐Wasels [6] was using carbogen breathing during radiotherapy to improve tumor oxygenation and radiation response in cancer patients.…”