Changes of Oxygen Tension in Tumours Induced by Vasoconstrictor and Vasodilator Drugs

Cater, D. B.; Grigson, C. M. B.; Watkinson, Douglas A.

doi:10.3109/00016926209169582

Cited by 73 publications

(21 citation statements)

References 27 publications

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“…It acts mainly on the vascular smooth muscle causing peripheral vaso-dilation and decreased arterial blood pressure. It is known that hydralazine reduces but does not completely occlude blood flow in some experimental tumours (Cater et al, 1962;Kruuv et al, 1967;Vorhees & Babbs, 1982;Chan et al, 1984;Chaplin & Acker, 1987). The data in Figure 3 show that hydralazine is effective in causing enhancement even when given before treatment with melphalan.…”

Section: Therapeutic Gainmentioning

confidence: 99%

“…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).…”

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confidence: 99%

“…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).…”

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

Stratford¹,

Adams²,

Godden³

et al. 1988

Br J Cancer

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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...

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Section: Therapeutic Gainmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Stratford¹,

Adams²,

Godden³

et al. 1988

Br J Cancer

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“…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.…”

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confidence: 99%

Cinnarizine and flunarizine as radiation sensitisers in two murine tumours

Wood

Hirst²

1988

Br J Cancer

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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...

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“…It has been known for many years that systemic administration of certain vasoactive drugs can result in selective reductions in tumour blood flow (Algire & Legallais, 1951;Cater et al, 1962;Cater et al, 1963;Knapp et al, 1985). One of the most effective agents in reducing blood flow to tumours without affecting normal tissue blood flow is 5-hydroxytryptamine (Cater et al, 1962;Cater et al, 1963;Cater et al, 1965: Knapp et al, 1985.…”

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

Chaplin¹

1986

Br J Cancer

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Changes of Oxygen Tension in Tumours Induced by Vasoconstrictor and Vasodilator Drugs

Cited by 73 publications

References 27 publications

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

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

Cinnarizine and flunarizine as radiation sensitisers in two murine tumours

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

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