Cinnarizine and flunarizine as radiation sensitisers in two murine tumours

Abstract

Summary The effect of the calcium antagonists, cinnarizine and flunarizine on the radiation sensitivity of two murine tumours, RIF-1 and SCCVII/St was investigated. Initial experiments giving the compounds at 50mgkg-1 i.p. indicated that cinnarizine had no effect on cell survival after 20Gy of X-rays in the RIF-1 sarcoma and only a small effect in the SCCVII/St carcinoma. However, flunarizine produced a small radiosensitisation in the RIF-1 tumour and a substantial sensitisation in the SCCVII/St tumour. Subsequent experiments in the SCCVII/St tumour indicated that the optimal radiosensitising dose of flunarizine was -55mg kg-1, although some sensitisation was apparent throughout the range of 0.05-500mg kg-1. Flunarizine produced a parallel shift in the X-ray dose response curve, equivalent to a 5-fold reduction in hypoxic fraction. In a normal tissue study, 5mgkg-1 flunarizine did not enhance the reduction in white cell counts produced by X-ray doses of 2-8 Gy. These data suggest that flunarizine may have some potential use as a radiosensitiser.Tumour blood flow is considered to be an important determinant in the outcome of treatment by a number of agents, including hyperthermia, chemotherapy and radiation. In the case of hyperthermia, poor tumour blood flow may enhance local heating (Knapp et al., 1985), whereas for chemotherapy, good blood flow to tumours may ensure the drug reaches its target, and for radiation, allow adequate oxygenation essential for effective radiotherapy.Most tumours exhibit a primitive vasculature (Cater et al., 1962), and therefore blood flow to the tumour is dependent to a large extent on the blood supply to the surrounding tissues.A large number of publications have been concerned with the effects of a range of systemically administered vasoactive compounds on the blood flow in tumours (Kruuv et al., 1967;Jirtle et al., 1978;Pallavicini & Hill, 1983), many with conflicting results. The general conclusion to be drawn is that the response is very much dependent upon the tumour system being studied (see Mattson & Peterson, 1981, for review).Nevertheless, alterations in tumour blood flow have recently been used to exploit the properties of certain therapeutic regimens. For example, Chaplin (1986) has found that 5-hydroxytryptamine (5HT) can enhance the effectiveness of the hypoxic cytotoxin, RSU 1069. Similarly Knapp et al. (1986) have used 5HT to enhance tumour response to hyperthermia. In both cases presumably 5HT is acting by decreasing blood flow to the tumour. In contrast, two other vasoactive agents, the calcium antagonists verapamil and flunarizine have been shown to increase tumour blood flow in experimental animals (Kaelin et al., 1982(Kaelin et al., , 1984. This property could therefore be exploited in radiation therapy, where enhanced tumour oxygenation brought about by the increase in tumour blood flow is advantageous.Flunarizine is a unique calcium antagonist in that its vasodilating properties are seen in the peripheral tissues at concentrations which have little effect o...

Cinnarizine and flunarizine improve the tumour radiosensitisation induced by erythrocyte transfusion in anaemic mice

“…The effect is not so pronounced as that reported for the cinnarizine and flunarizine radiosensitisation in normal mice (Wood & Hirst, 1988). The reason for this is not clear but may be related to the fact that in this study cinnarizine and flunarizine are being given to anaemic mice.…”

“…The time course for the effect of erythrocyte transfusion on tumour response to 20 Gy X-rays in anaemic mice has been reproduced in Figure (Wood & Hirst, 1988) and are reproduced with permission. In both cases radiosensitisation occurred, but the time course and the size of the effect were different for the two tumours.…”

“…This type of hypoxic cell may therefore be targeted by agents which increase tumour perfusion, such as some calcium antagonists. Two of these agents, verapamil and flunarizine, have been demonstrated to increase blood flow in experimental tumours (Kaelin et al, 1982(Kaelin et al, , 1984, and flunarizine has been shown to be an efficient radiosensitiser in murine tumours (Hill & Stirling, 1987;Wood & Hirst, 1988). If these two distinct subpopulations of hypoxic cells are present in the same tumour, then it follows that the combination of the two manipulations described above to reduce these subpopulations may enhance further the radiation sensitivity of the tumour.…”

“…This has been demonstrated by Hirst et al (1984), where alterations in host haematocrit had a large effect on tumour sensitivity to X-rays. In particular, the use of an erythrocyte trans fusion to restore the haematocrit of an anaemic, tumour bearing mouse produced a large increase in radiation sensitivity (Hirst & Wood, 1987 (Kaelin et al, 1982(Kaelin et al, , 1984, and flunarizine has been shown to be an efficient radiosensitiser in murine tumours (Hill & Stirling, 1987;Wood & Hirst, 1988). If these two distinct subpopulations of hypoxic cells are present in the same tumour, then it follows that the combination of the two manipulations described above to reduce these subpopulations may enhance further the radiation sensitivity of the tumour.…”

The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment

“…Flunarizine (E-1 -[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl)piperazine dihydrochloride) is a WHO class IV calcium-entry blocking agent which enhances radiosensitivity in vivo in animal models (Wood & Hirst, 1988). Numerous studies have demonstrated that the drug significantly improved blood flow and oxygenation in the hypoxic regions of tumours implanted experimentally in animals (Kaelin et al, 1984;Vaupel & Menke, 1987;Fenton & Sutherland, 1992).…”