Potentiation of the anti-tumour effect of melphalan by the vasoactive agent, hydralazine

Abstract

Summary The vaso-active drug hydralazine causes a considerable increase in the cytotoxic effect of melphalan towards the KHT tumour in mice. The enhancement in response, measured as the concentration of melphalan required to achieve a given tumour response, is 3.0 and 2.35 when determined using the regrowth delay assay and the technique for determining surviving fraction in vitro following treatment in vivo respectively. In contrast, measurement of systemic toxicity shows that the addition of hydralazine only causes a small increase (ER= 1.15) in melphalan damage. This suggests that the drug combination may have some therapeutic benefit. The tumour specificity for the action of hydralazine is supported by the finding that binding of 3H-misonidazole is increased in tumours but not in other tissues when mice are treated with hydralazine. Increased binding of labelled misonidazole is associated with an increase in the level and duration of hypoxia, which will occur as a consequence of changes in tumour blood flow brought about by hydralazine. However, hypoxia per se is not responsible for the enhanced effect of melphalan, since the agent BW12C, which also induces substantial tumour hypoxia as a result of changing the 02 affinity of haemoglobin, has no effect on melphalan tumour cytotoxicity.There have been various reports showing that vasoactive drugs can significantly affect the nature of blood flow in both experimental rodent and human tumours (Algire & Lagallais, 1951;Cater et al., 1962;Kruuv et al., 1967; Vorhees & Babbs, 1982;Knapp et al., 1985). Reduced blood flow in tumours can cause lowering of the oxygen status of the tumour, thereby causing radiation resistance (Kruuv et al., 1967). This so-called 'stealing' effect has recently been exploited by Chaplin and Acker (1987) in order to increase the anti-tumour effect of the bio-reductive agent, RSU 1069 (Adams et al., 1984) a compound which is activated under hypoxic conditions to give a species 100 x more toxic than the parent compound (Stratford et al., 1986).Reduction of blood flow in tumours may also be potentially useful for enhancing the effects of some anti-cancer drugs. The rationale for this is that, administration of the vaso-active drug at the time at which the chemotherapeutic agent has reached its maximum tumour concentration, will inhibit loss of active drug from the tumour. This could increase the overall exposure of the tumour cells to the cytotoxic drug. This paper describes the results of a study of the effect of the vasoactive agent hydralazine on the cytotoxic action of melphalan (L-phenylalanine mustard, L-PAM) towards the KHT sarcoma in mice. Materials and methodsMice and tumours Eight to 12 week old male Category IV C3H/He mice, obtained from NIMR, Mill Hill, London in 1984 and subsequently bred 'in-house', were used in the present experiments. The KHT sarcoma (Kallman et al., 1967), provided by Dr P. Twentyman, MRC, Cambridge in 1983, was maintained by inoculation of a tumour brei into the gastrocnemius muscle of female mice. Generall...

Induction of tumour hypoxia by a vasoactive agent A combined NMR and radiobiological study

“…This resistance has been attributed to the 'steal' phenomenon, whereby tumour perfusion is decreased when blood flow to other tissues is increased. Induction of severe hypoxia in tumours can greatly increase the effect of bioreductive agents [7,8].…”

Enhancement of chemotherapy and nitroimidazole-induced chemopotentiation by the vasoactive agent hydralazine

“…Previous investigations have shown that administering the vasoactive drug hydralazine after melphalan treatment can enhance the antitumour efficacy of this chemotherapeutic agent (Stratford et al, 1987(Stratford et al, , 1988Chaplin et al, 1989). Consequently, this was the first chemotherapeutic agent evaluated in the present studies.…”

“…The use of post-treatment hydralazine exposure has not, however, been restricted to the combination with bioreductive drugs. In addition, this treatment strategy has been shown to yield effective enhancement of selected chemotherapeutic agents and hyperthermia (Chaplin, 1987;Stratford et al, 1988 (Brown, 1982;McNally, 1982;Siemann, 1982Siemann, , 1984. Further, the majority of these investigations implicate hypoxia as a requirement for the expression of chemosensitisation (Siemann, 1984;Siemann & Mulcahy, 1986).…”

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

“…Horsman et al (1996) have shown that tumour blood flow changes brought about by nitro-L-arginine lasted no more than an hour, whereas the changes in redox status reported by Wood et al (1994a) could last for up to 6 h. Thus, the underlying mechanism mediating these anti-tumour effects is likely to be a complex interaction between hypoxia induction and entrapment (distribution and pharmacokinetics). Such interactions have been shown to contribute to the potentiation of the activity of both RSU1069 and the alkylating agent melphalan using a variety of techniques for modifying blood flow to tumours (Chaplin and Acker 1987;Stratford et al, 1988;Bremner et al, 1990;Castellino et al, 1995).…”