Warfarin Treatment of Mice Bearing Autochthonous Tumors: Effect on Spontaneous Metastases

Ryan, James J.; Ketcham, Alfred S.; Wexler, Hilda

doi:10.1126/science.162.3861.1493

Cited by 38 publications

(15 citation statements)

References 5 publications

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“…The effect on metastasis was not as dramatic as that seen when tumour cells were injected intravenously in the same model system (McCulloch & George, 1987) but was consistent on subsequent repetition of the experiment. These findings are in agreement with those of Colucci et al (1983), but contrast with those of other workers (Ryan et al, 1968;Hilgard et al, 1977). Several of these previous studies used mouse models, in which a very much higher degree of anticoagulation could be achieved, and this may explain their contrasting outcomes.…”

Section: Discussionsupporting

confidence: 89%

“…The variety of models employed and the frequent use of in vitro measures of cytotoxicity without reference to the effects of the drugs in vivo make interpretation of these studies particularly difficult. Several studies have noted a possible suppressive effect of coumarin treatment on primary tumour growth (Ryan et al, 1968(Ryan et al, , 1969Hilgard et al, 1977), but have used only crude methods which are prone to random error. Only one study has attempted to combine in vitro studies of cytotoxicity and in vivo assessment of drug effects on tumour growth and metastasis (Brown, 1973) and the metastatic behaviour of the tumour model used makes interpretation of this study difficult.…”

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confidence: 99%

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Warfarin inhibits metastasis of Mtln3 rat mammary carcinoma without affecting primary tumour growth

McCulloch

George²

1989

Br J Cancer

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Summary Coumarin anticoagulants inhibit metastasis in several animal models, but the mechanism of this effect is uncertain. In order to determine the role of cytotoxic and/or cytostatic actions of coumarins on the tumour cells, we have studied the effects of warfarin on tumour cell growth in a model in which tumour metastasis is inhibited by this drug. Clonogenic assay, growth curve analysis and thymidine labelling index revealed that warfarin had no effects on Mtln3 mammary carcinoma cell growth in vitro at concentrations below 1 mm. The growth rate of subcutaneously implanted Mtln3 tumour deposits in female F344 rats, assessed by weight and by stathmokinetic analysis of the tumour tissue, was identical in warfarin-treated and control animals. Spontaneous metastasis from such tumours to the lungs was, however, significantly reduced in warfarin-treated animals (median 0 pulmonary tumours per animal in warfarin treated, eight tumours per animal in control animals; P<0.05, Mann-Whitney). The mean plasma warfarin concentration in warfarin treated rats was 1.63 M. These results suggest that warfarin treatment of the host animal can inhibit tumour metastasis without having any direct or indirect effect on the growth rate of the tumour cells.Current theories (Hart, 1980;Poste & Fidler, 1980) view metastasis as a multistep process in which successive obstacles are overcome by a small subpopulation of tumour cells capable of doing so. Each step requires different properties, and each influences subsequent steps. This complex process cannot be studied as a single unit, but requires subdivision: one way in which this can be achieved is to study influences that increase or decrease metastasis, and to attempt to define the point at which they have their effect. The coumarin group of anticoagulant drugs, including warfarin, represent an example of such an influence. Coumarins inhibit metastasis in several animal models (Ryan et al., 1969;Brown, 1973;Hilgard et al., 1977;Williamson et al., 1980). There is an extensive literature documenting the existing of coagulation disturbances in human cancer (Davis et al., 1969;Sun et al., 1979;Rickles & Edwards, 1983; Mannucci et al., 1985), and suggestive evidence of a role for coagulation in the spread and growth of tumours (Dvorak et al., 1979; Goeting et al., 1985;McCulloch & George, 1987 (Colucci et al., 1983). The possibility that coumarins have cytotoxic properties has been investigated in several different models (Boulos, 1971;Higashi & Heidelberger, 1971;Brown, 1973;Chang & Hall, 1973;Dolfini et al., 1979;McNeil et al., 1984) with diverse results. The variety of models employed and the frequent use of in vitro measures of cytotoxicity without reference to the effects of the drugs in vivo make interpretation of these studies particularly difficult. Several studies have noted a possible suppressive effect of coumarin treatment on primary tumour growth (Ryan et al., 1968(Ryan et al., , 1969Hilgard et al., 1977), but have used only crude methods which are prone to random error. On...

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Warfarin inhibits metastasis of Mtln3 rat mammary carcinoma without affecting primary tumour growth

McCulloch

George²

1989

Br J Cancer

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“…We are currently investigating the relation between naturally occurring fibrinolysis and the release of malignant cells at operation in man.2" Fearnley and Chakrabatti7 have described a case of metastatic breast cancer treated with testosterone in whom an increase in fibrinolytic activity was followed by clinical improvement and radiologic regression of bony lesions. Michaels13 and Ryan et al 17 have reported a lower mortality from carcinoma and a lower than expected incidence of metastases in patients receiving long-term oral anticoagulants for thrombotic disorders. Nevertheless, the role of fibrinolysis in the inhibition or potentiation of the spread of malignant disease in man remains an open question.…”

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confidence: 98%

Carcinoma of the colon and rectum: Circulating malignant cells and five-year survival

Griffiths

McKinna

Rowbotham

et al. 1973

Cancer

109

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Circulating malignant cells are found infrequently in the peripheral blood of patients with carcinoma of the colon and rectum. The incidence rises on induction of anesthesia (28%), and tumor cells can be identified in the peripheral blood of 50% of patients during surgery. Some of the important features in their cytologic identification (and distinction from other large mononu‐clear cells) are reported. There is a 57% yield when the blood sample is taken from the inferior mesenteric vein draining the tumor in the rectum or left colon. Five‐year follow‐up on two series of 50 patients shows that the detection of circulating malignant cells has no prognostic significance, and it is not related to the presence of histologic evidence of venous invasion, although this invasion itself is associated with a worse outlook. Fifty‐six per cent of patients in whom circulating tumor cells were found at surgery are alive and well without sign of recurrence or metastasis. In cases where blood samples were taken from the common or internal iliac vein before and after ligation of the inferior mesenteric vein, it was noted that patients with no detectable circulating tumor cells had a tendency towards liver metastases, whereas those showing circulating cells in pelvic veins, only after mesenteric vein ligation, had a tendency towards systemic bony deposits. During the isolated perfusion of excised tumors, it was found that addition of a fibrinolytic agent caused the liberation of large numbers of cells. Naturally occurring fibrinolysis may play a part in the liberation of cells into the bloodstream and in their subsequent ability to establish metastases.

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“…DHHS and by a grant from the National Foundation for Cancer Research. shielding the tumor mass from host defenses and therapeutic intervention with a fibrin 'cocoon' [18]. Anticoagulants have been ob served to inhibit experimental tumors [16,31,38,42,61,71], and in combination with other regimens, the oral anticoagulant so dium warfarin (Coumadin) has been effective against some types of cancer in clinical trials [17, 85, 92a, b]. However, the mechanism of this inhibition has not been established.…”

Section: Introductionmentioning

confidence: 99%

Vitamin K-Dependent Processes in Tumor Cells

Hauschka¹,

Haroon²,

Buchthal

et al. 1986

Pathophysiol Haemos Thromb

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Tumor cells are known to interfere with blood coagulation pathways of the host by producing procoagulants and other substances, thereby deriving certain advantages relating to tumor growth, metastasis, and angiogenesis. Anticoagulants may diminish these advantages under certain conditions. The interaction between coumarin anticoagulants and tumor cells has been reviewed with respect to procoagulants and their vitamin K-dependent properties. Evidence is also presented which suggests that vitamin K-dependent protein carboxylation is a general property of tumor cells.

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Warfarin Treatment of Mice Bearing Autochthonous Tumors: Effect on Spontaneous Metastases

Cited by 38 publications

References 5 publications

Warfarin inhibits metastasis of Mtln3 rat mammary carcinoma without affecting primary tumour growth

Warfarin inhibits metastasis of Mtln3 rat mammary carcinoma without affecting primary tumour growth

Carcinoma of the colon and rectum: Circulating malignant cells and five-year survival

Vitamin K-Dependent Processes in Tumor Cells

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