Effects of verapamil and alcohol on blood flow, melphalan uptake and cytotoxicity, in murine fibrosarcomas and human melanoma xenografts

Robinson, Bridget A.; Clutterbuck, R. D.; Millar, J. L.; McElwain, T. J.

doi:10.1038/bjc.1986.103

Cited by 8 publications

(1 citation statement)

References 23 publications

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“…Similarly, the vaso-dilating agent, verapamil, also increases the cytotoxicity of melphalan in some experimental tumours and some normal tissues (Robinson et al, 1985). In this latter study it was shown that the effect of verapamil is to change melphalan pharmacokinetics and cellular uptake rather than causing any alterations in tumour blood flow (Robinson et al, 1985(Robinson et al, , 1986.…”

Section: Therapeutic Gainmentioning

confidence: 76%

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: 76%

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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Blood flow measurement in extremity soft tissue sarcoma with technetium-99m hexamethyl-propyleneamineoxime and single photon emission computed tomography

Hill

Flower

Cronin

et al. 1994

Journal of British Surgery

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Blood flow measurements were made in 28 patients with soft tissue sarcoma of the extremities to investigate the prognostic significance of tumour vascularity. Four patients with benign tumours also underwent blood flow measurement. Mean and maximum tumour blood flow was calculated from technetium-99m hexamethyl-propyleneamineoxime uptake measured using single photon emission computed tomography (SPECT), tumour volume measured from SPECT transaxial image reconstructions and cardiac output assessed with Doppler ultrasonography. Twenty-seven malignant lesions and one benign tumour showed increased uptake of isotope relative to surrounding tissues. Mean sarcoma blood flow varied between 1 and 33 ml per 100 ml tumour per min, and maximum flow between 5 and 57 ml per 100 ml per min. Fourteen patients developed progressive disease during the first year of follow-up. Eight of 11 patients with a high isotope uptake ratio, eight of 12 with a high mean blood flow and eight of 14 with a high maximum blood flow relative to the respective medians for the series showed disease progression.

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Blood Flow, Vascular Resistance and Oxygen Availability in Malignant Tumours upon Intravenous Flunarizine

Vaupel

Menke

1987

Oxygen Transport to Tissue IX

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Effects of verapamil and alcohol on blood flow, melphalan uptake and cytotoxicity, in murine fibrosarcomas and human melanoma xenografts

Cited by 8 publications

References 23 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

Blood flow measurement in extremity soft tissue sarcoma with technetium-99m hexamethyl-propyleneamineoxime and single photon emission computed tomography

Blood Flow, Vascular Resistance and Oxygen Availability in Malignant Tumours upon Intravenous Flunarizine

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