Potentiation of RSU-1069 tumour cytotoxicity by 5-hydroxytryptamine (5-HT)

SummaryThe tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA) causes dramatic haemorrhagic necrosis in murine tumours, but activity is seen only at doses close to the toxic limit. This study investigates two approaches for increasing the therapeutic ratio of DMXAA. The first approach combines DMXAA with a second tumour blood flow inhibitor, 5-hydroxytryptamine (5-HT). Co-administration of 5-HT (700,mol kg-1) to C3H mice caused marked enhancement of DMXAA effects against MDAH-MCa-4 tumours, with dose-modifying factors (DMFs) of >3 for blood flow inhibition (at 4 h), 2.3 for necrosis (at 12 h) and 2.0 for growth delay, without compromising the maximum tolerated dose of DMXAA (90 gmol kg-'). The data are consistent with ischaemic injury to the tumour being the major mechanism of antitumour activity. The second approach combines DMXAA (± 5-HT) with hypoxia-selective bioreductive drugs. Anti-tumour activity of all three bioreductive drugs tested (tirapazamine, Cl-1010, SN 23816) was strongly potentiated by DMXAA, suggesting that there is a population of reversibly hypoxic tumour cells after DMXAA treatment. Co-administration of 5-HT further potentiated anti-tumour activity, but also increased host toxicity of tirapazamine and Cl-101 0 so that little therapeutic benefit was achieved. In contrast, the host toxicity of the dinitrobenzamide mustard SN 23816 was only slightly increased by DMXAAI5-HT, whereas the tumour growth delay at the maximum tolerated dose of SN 23816 was increased from 3.5 to 26.5 days. This study demonstrates that 5-HT and/or bioreductive drugs can improve the therapeutic activity of DMXAA in mice, and that with SN 23816 both approaches can be used together to provide considerably enhanced anti-tumour activity.

mentioning

confidence: 99%

Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs

Lash

Li²,

Rutland³

et al. 1998

“…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.…”

mentioning

confidence: 99%

Cinnarizine and flunarizine as radiation sensitisers in two murine tumours

Wood

Hirst²

1988

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...

“…Such reductions can lower the oxygen status of tumours and thereby cause radiation resistance (Kruuv et al, 1967;Stratford et al, 1989). This so-called 'stealing effect' has been exploited to increase the anti-tumour efficiency of various bioreductive drugs (Chaplin, 1986(Chaplin, , 1989. One of the largest enhancements was obtained by combining hydralazine with RSU1069 (Chaplin and Acker, 1987).…”

mentioning

confidence: 99%

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

Butler

Wood²,

Cole³

et al. 1997

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.