The effect of very-low-dose warfarin on markers of hypercoagulation in metastatic breast cancer: results from a randomized trial.

Malignancy is a risk factor for thromboembolism and anti-cancer chemotherapy can increase this risk. Prophylaxis of thrombosis with very-low-dose warfarin given concurrently with chemotherapy has a significantly reduced rate of thromboembolism in a randomized trial in women with stage IV breast cancer. In a group of 32 patients randomized in one center (16 subjects on warfarin and 16 on placebo), we have prospectively studied the plasma levels of: 1. Markers of 'in vivo' clotting activation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1+2] and D-dimer), 2. Factor VII (FVII), and 3. Natural anticoagulants (protein C [PC] and antithrombin [AT]). The aims of this study were: 1. to examine whether laboratory tests predicted those patients who developed thrombosis, and 2. to evaluate the effect of very-low-dose warfarin on hemostatic variables. The patients' hemostatic parameters were evaluated before entry into the study and after starting chemotherapy +/- prophylaxis, before each course for nine courses. Before-treatment results were compared to those of a sex and age-matched non-cancer control group. There was a significant elevation of plasma levels of TAT (p <0.001), F1+2 (p <0.001), D-dimer (p <0.0001) and FVIIa (p <0.05), as well as an increase of FVII proteolysis (p <0.05), whereas plasma PC and AT concentrations were not different from controls. After starting chemotherapy, markers of clotting activation were progressively lower in the group receiving warfarin prophylaxis compared to the group on placebo. Differences between the groups became statistically significant (p <0.01) after the 4th course of chemotherapy. Deep vein thrombosis occurred in two patients in the placebo arm. The results of this study indicate that before therapy, an hypercoagulable state is present in stage IV breast cancer, and after starting chemotherapy, abnormalities of hypercoagulation markers persist, however they are reduced by very-low-dose-warfarin. None of the laboratory variables could predict thrombosis in the single patient.

Hemostatic system activation in patients with lupus anticoagulant and essential thrombocythemia.

Hemostatic system activation was estimated in the plasmas of 39 patients with LAC and 19 patients with ET by measuring concentrations of TAT complex and prothrombin F1+2. The concentrations of FVII, recognized previously as a risk factor for arterial thrombosis, were also measured. None of the patients had active thrombosis during this study. The mean TAT and F1+2 levels in LAC and ET plasmas were higher than the respective values in the plasmas of healthy control subjects. Compared with their respective controls, TAT levels were significantly higher in the LAC group (P < 0.05) and F1+2 was significantly higher in the ET group (P < 0.005). The mean FVIIt and FVIIz was significantly higher (P < 0.05 and P < 0.01, respectively) in LAC than control plasmas. Furthermore, the differences between FVIIt and FVIIz were significantly greater in LAC than control plasmas, indicating increased in vivo proteolysis of FVII in LAC. Although the mean concentrations of these two FVII parameters in ET plasma were not significantly different from those of normal plasmas, the FVII levels were higher in 30% of ET plasmas than the upper limit of controls. Our results are consistent with hypercoagulation in LAC and ET patients, and this may be a contributory factor for the increased rates of thrombosis associated with the two conditions.

The hypercoagulable state in cancer patients: evidence for impaired thrombin inhibitions.

Activation of prothrombin and the subsequent reactions of thrombin with its substrates and its major inhibitors, antithrombin III (AT III) and heparin cofactor II (HC II), likely reflect both intravascular and extravascular coagulation. Several studies have reported increased in vivo coagulation in cancer. Whether the increased thrombin production in malignancy is accompanied by a corresponding increase in thrombin inhibition is unknown. This study quantified prothrombin fragment 1 + 2 (F1 + 2), thrombin-AT III (TAT), thrombin-AT III-vitronectin (TAT.V), and thrombin-HC II-vitronectin (THCII.V) in the plasmas of healthy volunteers (n = 37); patients with localized solid tumours before treatment was initiated (n = 39); and five patients with non-Hodgkin's lymphoma, both before and during weekly chemotherapy. Two of the five non-Hodgkin's lymphoma patients developed deep venous thrombosis (DVT) during chemotherapy. In normal plasma, where the concentrations of the four parameters likely reflect haemostasis, the sum of TAT, TAT.V and THCII.V was 61% that of F1 + 2, compared with 30% in cancer plasmas. In addition, the mean +/- SEM of F1 + 2 in the plasmas of cancer patients (1.56 +/- 0.09 nM) was significantly elevated (P < 0.001) when compared with healthy volunteers (0.89 +/- 0.06 nM). Eight weeks of chemotherapy increased the F1 + 2 and the binary TAT in plasmas of the non-Hodgkin's lymphoma patients by approximately 1.5- and 2.9-fold, respectively. Thus, increased prothrombin activation in cancer patients, without corresponding increases in concentrations of thrombin-inhibitor complexes, raise the possibility that a significant portion of the thrombin generated in vivo escapes inhibition in cancer and contributes to the high risk of DVT in malignancy.

Preliminary study to identify cancer patients at high risk of venous thrombosis following major surgery.

This study investigated whether the pre-surgical plasma levels of TAT and F1 + 2 of patients undergoing major surgery for localized tumours could identify patients at higher risk of thrombosis, and how heparin prophylaxis affected in vivo coagulation after cancer surgery. We measured the pre- and post-operative levels of TAT, F1 + 2, total factor VII (FVIIt) and zymogen FVII (FVIIz) in 117 cancer patients, with and without heparin prophylaxis. The end points of this study were DVT, initially detected by 125I-fibrinogen uptake test and confirmed by ascending venography. Pre-operative [TAT] and [F1 + 2] of the cancer patients were significantly higher than those of age-matched control subjects (n = 50) (P < 0.005 and P < 0.05, respectively); pre-operative [FVII] was not significantly different. One of the 83 patients receiving prophylaxis, and 8/34 not receiving prophylaxis developed post-operative DVT. Of the parameters evaluated, only the pre-operative [TAT] > 3.5 ng/ml identified patients at higher risk for post-operative DVT. Heparin reduced plasma TAT levels and FVII consumption following surgery, suggesting that heparin modulates coagulation associated with cancer surgery. The results of this study also suggest that the pre-operative [TAT] may identify patients with higher risk for post-operative DVT.

Blunted excretory response to atrial natriuretic peptide in experimental nephrosis.

Adriamycin (ADR) nephrosis and a model of unilateral ADR-induced proteinuria were produced in Sprague-Dawley (S.D.) rats to investigate the mechanism of sodium retention by the nephrotic kidney. Plasma volume, as measured by the dilution principle using radioiodinated serum albumin, was significantly higher in nephrotic animals than in control ones (NS: 69.61 +/- 15.02: control: 47.05 +/- 5.32 ml/kg: P less than 0.01). Similarly plasma levels of immunoreactive ANP (iANP) were significantly higher in nephrotic animals compared to controls (NS 104.22 +/- 36.41: control 59.94 +/- 20.88 pg/ml; P less than 0.05). Using the unilateral model we found a markedly reduced diuretic and natriuretic response to the infusion of synthetic rat atrial natriuretic peptide (ANP 1-28) in proteinuric kidney but not in contralateral kidney, despite a comparable increase in glomerular filtration rate. To explain the blunted diuresis and natriuresis in the presence of normal glomerular response to ANP, we investigated the possibility of an abnormality at post-glomerular level by studying ANP receptor density and affinity of the inner stripe of outer medulla and the inner medulla in ADR-and vehicle-treated rats. The inner stripe of outer medulla and the inner medulla receptor density and affinity were not significantly different in ADR rats as compared to animals given the vehicle alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Tertatolol ameliorates renal function in rats with chronic renal failure.

Tertatolol is a new beta-blocking agent which induces renal vasodilation in experimental animals and humans and increases glomerular filtration rate (GFR), diuresis and natriuresis. The mechanisms underlying renal effects of tertatolol are not known. Our aims were to establish whether tertatolol influences renal function by a systemic or by an intrarenal effect and to assess whether tertatolol could maintain GFR in chronic renal failure. Tertatolol but not propranolol when given as i.v. bolus injection at the dose of 25 and 50 micrograms/kg. b.w. induces a significant increase in GFR and perfusate flow rate (PFR) in an isolated perfused kidney model [GFR: tertatolol, 25 micrograms/kg; preinjection: 0.477 +/- 0.077 ml/min/g of kidney; 30 min postinjection: 0.996 +/- 0.114 ml/min/g of kidney. Tertatolol (50 micrograms/kg) preinjection: 0.517 +/- 0.040 ml/min/g of kidney; 30 min postinjection: 0.879 +/- 0.035 ml/min/g of kidney. Propranolol (500 micrograms/kg) preinjection: 0.574 +/- 0.045 ml/min/g of kidney; 30 min postinjection: 0.538 +/- 0.029 ml/min/g of kidney. PFR: tertatolol, 25 micrograms/kg, preinjection: 30.00 +/- 0.79 ml/min; 30 min postinjection: 36.20 +/- 2.58 ml/min. Tertatolol (50 micrograms/kg) preinjection: 29.30 +/- 1.44 ml/min; 30 min postinjection: 38.01 +/- 1.87 ml/min. Propranolol (500 micrograms/kg) preinjection: 28.70 +/- 1.04 ml/min; 30 min postinjection: 28.30 +/- 0.91 ml/min]. In the same preparation tertatolol significantly increases urine flow rate and Na+ excretion [urine flow rate: tertatolol (25 micrograms/kg) preinjection: 28.28 +/- 4.10 microliter/min; 60 min postinjection: 38.23 +/- 6.74 microliter/min. Tertatolol (50 micrograms/kg) preinjection: 24.02 +/- 0.63 microliter/min; 60 min postinjection: 33.18 +/- 2.07 microliter/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of platelet-activating factor and its specific receptor antagonist on glomerular permeability to proteins in isolated perfused rat kidney.

Platelet-activating factor (PAF) is a lipid mediator of inflammation believed to play a role in glomerulonephritis by favoring immune complex formation and modulating the subsequent inflammatory reaction. Some evidence indicates that PAF may also be one of the mediators of proteinuria. Previous work suggested that PAF can increase glomerular permeability to proteins, activating platelets and inflammatory cells to release cationic proteins. In the present study, we addressed the possibility that PAF might directly increase glomerular permeability to proteins independently of platelets and inflammatory cells. We used a preparation of isolated rat kidney perfused with an artificial cell-free medium. After stabilization and two 10-minute control clearance periods, kidneys perfused in a closed circuit were exposed to PAF (2 nM or 10 nM final concentration) or 2-lyso-PAF (10 nM final concentration) or vehicle for 40 minutes. Glomerular filtration rate, measured as creatinine clearance, and renal vascular resistance did not significantly change when either PAF (2 nM or 10 nM) or 2-lyso-PAF, or vehicle were added to the perfusion fluid. Unlike vehicle or 2-lyso-PAF, addition of PAF at the final concentration of 2 and 10 nM to the perfusate produced a dose-dependent progressive increase in urinary protein excretion. PAF-induced proteinuria was prevented by L-652,731, a specific PAF receptor antagonist, suggesting that PAF's effect on glomerular permeability to proteins is likely to be related to its biologic activity. Several pharmacologic manipulations addressed to the potential mediators of PAF effect on glomerular permeability to proteins would exclude that the effect of PAF on isolated perfused kidney is mediated by cyclooxygenase or lipoxygenase products, or is the result of oxygen-free radical generation. The possibility that PAF enhances glomerular permeability to proteins by changing the glomerular barrier electrostatic properties was explored using polyethylene-imine. Electron microscopy examination revealed no difference in the distribution of electron-dense deposits along the glomerular basement membrane in kidneys exposed to 10 nM PAF or vehicle.

Renal response to atrial peptides is reduced in experimental nephrosis.

The aim of this study was to evaluate the renal response to atrial extracts (AE) and synthetic atrial natriuretic factor (ANF) in control rats and in rats with experimental nephrotic syndrome (NS). NS was obtained by a single intravenous injection of adriamycin (7.5 mg/kg). Bolus injection of AE from normal or NS rats resulted in marked increase of diuresis and natriuresis in bioassay control rats (AE from normal rats, urine flow rate, 14.87 +/- 2.94 to 186.18 +/- 55.86 microliters/min; Na excretion, 0.68 +/- 0.26 to 21.80 +/- 5.45 mu eq/min; AE from NS, urine flow rate, 13.49 +/- 4.30 to 167.14 +/- 51.44 microliters/min; Na excretion, 0.98 +/- 0.57 to 20.71 +/- 9.76 mu eq/min). In contrast, blunted diuretic (from 11.26 +/- 3.05 to 65.20 +/- 27.30 microliters/min) and natriuretic (from 0.58 +/- 0.15 to 4.52 +/- 1.59 mu eq/min) effect was observed when AE were injected in rats with NS. Injection of the vehicle in which AE were dissolved or ventricular extracts did not increase urinary flow rate or Na excretion in both control and NS animals. Bolus injection of synthetic ANF (Arg-101-Tyr-126) induced marked diuretic and natriuretic response in control but not in NS rats. Similar results were obtained when AE were infused by constant infusion in control or in NS bioassay rats. AE given by constant infusion induced comparable increase in glomerular filtration rate (GFR) over basal values both in control and NS animals (controls, 39%; NS rats, 40%).(ABSTRACT TRUNCATED AT 250 WORDS)

Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A.

Animals and humans undergoing a chronic treatment with cyclosporin A (CyA) show a reduction in glomerular filtration rate (GFR). The cause of this abnormality has not been established. Since CyA interferes with arachidonic acid (AA) metabolism in various cells, we wished to determine whether alterations in renal AA metabolites contribute to deteriorating renal function in rats on CyA. We show that chronic CyA treatment induces a progressive increase in the renal synthesis of thromboxane (TX) A2. This is a selective abnormality in that CyA does not influence the renal synthesis of prostaglandin E2 (PGE2) and prostacyclin (PGI2). A significant negative correlation has been found between TXB2 urinary excretion rate and inulin clearance. No correlation has been observed between TXB2 excretion and p-aminohippuric acid clearance. The withdrawal of CyA is followed by a normalization of both TXB2 urinary excretion rate and GFR. The administration of a selective TXA2 inhibitor, UK-38,485, resulted in a significant reduction in urinary excretion of TXB2 accompanied by a significant increase in GFR. We conclude that chronic treatment with CyA in rats is associated with a selective increase in renal TXA2 synthesis and suggest that this abnormality may play a role in the reduction of GFR.

Platelet survival and function in rats with enhanced thrombotic tendency.

We have investigated the relevance of some laboratory tests of platelet function in predicting conditions of thrombotic tendency. For this purpose, we studied platelet survival, platelet aggregation in response to different stimuli, TxB2 and 6-keto-PGF1 alpha production in serum of rats bearing a nephrotic syndrome induced by adriamycin. These animals show a heavy predisposition to the development of both arterial and venous thrombosis. The mean survival time was normal in nephrotic rats in comparison to controls. As to aggregation tests, a lower aggregating response was found in ADR-treated rats using ADP or collagen as stimulating agents. With arachidonic acid (AA) we observed similar aggregating responses at lower AA concentrations, whereas at higher AA concentrations a significantly lower response was found in nephrotic rats, despite their higher TxB2 production. Also TxB2 and 6-keto-PGF1 alpha levels in serum of nephrotic rats were significantly higher than in controls. No consistent differences were found in PGI2-activity generated by vessels of control or nephrotic rats. These data show that platelet function may appear normal or even impaired in rats with a markedly increased thrombotic tendency. On the other hand, the significance of high TxB2 levels in connection with mechanisms leading to thrombus formation remains a controversial issue.

The effect of vitamin E or selenium on the oxidant-antioxidant balance in rats.

Vitamin E and selenium are two components which contribute to the antioxidant potential of plasma and tissues. In the present study we aimed to define the type of tissue toxicity deriving from chronic deficiency of either vitamin E or selenium and to evaluate the reliability of peripheral markers of tissue toxicity in these conditions. We studied rats fed a vitamin E or selenium-deficient diet for 3 or 7 months and a selenium-supplemented diet. The effectiveness of the dietary treatment was confirmed by measuring vitamin E and selenium in plasma. Heart and kidney malondialdehyde (MDA), a typical product of lipid peroxidation, was significantly increased after the 3-month diet in both vitamin E- and selenium-deficient rats. The iron-binding capacity of plasma, an activity ascribed to plasma transferrin, was reduced in selenium-deficient and increased in selenium-supplemented animals. In red cells globular resistance (resistance to osmotic haemolysis) was low in vitamin E- and selenium-deficient, but high in selenium-supplemented animals. Glutathione peroxidase was also increased in selenium-supplemented rats. Platelet count did not differ from controls in any of the three conditions studied. Platelet MDA formation induced by arachidonic acid was raised in both selenium-deficient and, particularly, vitamin E-deficient groups. This can be regarded as a peripheral marker of reduced antioxidant defence at tissue level.

Steroids and Adriamycin nephrosis.

Adriamycin induces a nephrotic syndrome in rats characterized by severe ultrastructural changes of visceral epithelial cells similar to those observed in puromycin aminonucleoside (PA) nephrosis and in human 'minimal changes' glomerulopathy. Since steroids have been shown to be effective in human 'minimal changes' glomerulopathy and in PA nephrosis, we undertook the present study to assess whether steroids had a therapeutic effect on adriamycin nephrosis. Groups of rats injected with different doses of adriamycin were subsequently treated with prednisolone. No significant differences were observed in proteinuria and in ultrastructural findings between the control and the steroid-injected animals. This study suggests that the mechanism underlying adriamycin-induced nephrotic syndrome might be different from that responsible for PA nephrosis or human 'minimal changes' glomerulopathy.

Unbalanced plasma control of TxA2 and PGI2 synthesis in vitamin E-deficient rats.

Factors contributing to the antioxidant power of plasma may play a role in the control of arachidonic acid (AA) metabolism. The purpose of this study was to evaluate the possible effects of vitamin E deficiency on platelet and vascular prostaglandin synthesis. CD-COBS male rats were fed for 7 mo a diet containing either 1 or 75 mg/kg vitamin E. At the end of this period, serum levels of vitamin E were 0.4 +/- 0.1 and 10 +/- 0.6 micrograms/ml in the two groups, respectively. Malondialdehyde (MDA) generation by AA was significantly higher in platelet-rich plasma from vitamin E-deficient rats. Thromboxane B2 (TxB2) in serum from vitamin E-deficient rats increased about 16 times compared with controls, whereas 6-keto-PGF1 alpha levels increased only 3 times. The ratio between TxB2 and 6-keto-PGF1 alpha, increased therefore manyfold in vitamin E-deficient animals. MDA formation and [14C]AA metabolism in washed platelets were similar in the two groups of animals. No significant difference was found in the PGI2 (prostacyclin) antiaggregating activity released from the aortic rings resuspended in buffer. In contrast, the capacity of plasma to stimulate PGI2 activity from "exhausted" aortic rings (prostacyclin-stimulating factor) was significantly reduced in vitamin E-deficient animals. In conclusion, vitamin E deficiency induces an unbalanced plasma regulation of AA metabolism. This results in an excessive production of platelet TxA2 compared with vascular PGI2 generation. On the other hand, vitamin E deficiency does not seem to affect directly the enzymatic pathways of AA metabolism.

Warfarin inhibits both procoagulant activity and metastatic capacity of Lewis lung carcinoma cells. Role of vitamin K deficiency.

Chronic vitamin K deficiency, either dietary or pharmacologically induced with warfarin, depressed significantly the growth of lung secondaries in a spontaneously metastasizing murine tumor, the Lewis Lung Carcinoma. This effect was associated with a marked depression of the procoagulant activity of cancer cells, which could contribute to fibrin deposition around the tumor. Cellular anticoagulation may thus be an important mechanism in the antimetastatic effect of warfarin.

The influence of selenium intake on chronic adriamycin toxicity and lipid peroxidation in rats.

This paper reports on the influence of selenium intake on antioxidant protective systems during chronic adriamycin (AM) treatment in rats. Rats were kept for 14 weeks on a selenium deficient (Se-) diet or a diet containing selenium (Se+). No significant differences were found in any group with regard to the cardiac content of total and reduced glutathione (GSH) and heart superoxide dismutase specific activity. AM treatment did not modify lipid peroxidation as measured by cardiac malondialdehyde (MDH) formation in rats receiving either the Se- or the Se+ diet. In the Se+ rats AM had no effect on the exhalation of ethane or pentane but decreased the exhalation of ethane and increased that of pentane in the SE- rats. In Se- AM-treated rats mortality was higher. Since this did not seem to be correlated with modifications of any of the biochemical parameters taken into consideration, it is suggested that the better resistance of Se+ animals to AM treatment is related to some factors not yet identified.

Severe glomerular epithelial cell damage does not prevent passive Heyman nephritis in rats.

Passive Heymann nephritis (PHN) is an experimental model of membranous glomerulopathy in the rat ascribed to in situ formation of immune complexes. Very recently the demonstration that the aminonucleoside of puromycin provides some protection against PHN has highlighted the role of intrinsic properties of the glomerulus in immune complex formation. Adriamycin, a widely employed chemotherapeutic agent, is known to induce a nephrotic syndrome in rats characterized by severe ultrastructural changes of glomerular epithelial cells and by loss of glomerular polyanionic charges. We have studied the effect of pre-treatment with adriamycin on glomerular immune deposits in PHN using immunomorphological and quantitative techniques. In normal rats (group 1) injection of heterologous antibodies to proximal tubular brush border antigen (anti-FxIA), rapidly induces subepithelial immune deposits, as observed by immunofluorescence. Pre-treatment of rats with adriamycin (group 2) 48 hr before injection of anti-FxIA antibodies, when proteinuria is absent, does not alter the immunohistological findings of PHN. Heavily proteinuric rats (group 3) pre-treated with adriamycin 13 days before injection of anti-FxIA did not show any significant difference from groups 1 and 2. Species binding of injected anti-FxIA antibodies, studied by paired label techniques, was similar in normal rats and in proteinuric and non-proteinuric rats treated with adriamycin. The only difference was in the group of proteinuric rats treated with adriamycin, in which at 5 hr binding in the kidney was higher, due to tubular brush border binding as shown by immunofluorescence. This study indicates that local changes of the glomerulus and loss of glomerular histochemical properties do not invariably alter the glomerular deposition of immune complexes.

Enhanced affinity for arachidonic acid in platelet-rich plasma from rats with Adriamycin-induced nephrotic syndrome.

We have measured the response to arachidonic acid (AA) in platelet-rich plasma (PRP) of rats with Adriamycin-induced nephrotic syndrome. For this purpose we measured the kinetics of generation of malondialdehyde (MDA), a stable product of cyclooxygenase activity, in response to platelet stimulation with different concentrations of the substrate. The apparent Km of platelet cyclo-oxygenase for AA was similar in PRP from control rats and rats treated 1-5 days previously, whereas it was significantly reduced, as compared to controls, in PRP of rats treated 2-5 weeks previously. Such a difference was not observed when washed platelet suspensions were tested instead of PRP. Experiments with crossed platelet/plasma systems indicated that in rats treated from 2-5 weeks, a plasmatic abnormality was indeed responsible for the increased affinity of platelets for AA. It is conceivable that in this nephrotic syndrome model characterized by heavy proteinuria, some plasmatic component would be lost with the urine which is normally modulating the platelet response to AA. The observed increase in platelet affinity for AA could at least partially contribute to the enhanced thrombotic tendency reported in the same experimental model.

Adriamycin-induced nephrotic syndrome in rats: sequence of pathologic events.

Adriamycin has been suspected of causing experimental nephrotoxicity. We report here that adriamycin induces a nephrotic syndrome in rats, proteinuria beginning 4 to 5 days after a single intravenous injection (7.5 mg. per kg. of body weight). The full expression of the syndrome develops 13 to 15 days later. Minimal alterations at light microscopy, negative immunofluorescence, and only some focal "fusion" of foot processes can be observed by electron microscopy in the early phase after injection (28 hours). At 13 days, loss of foot process architecture, and replacement by flattened epithelial cytoplasm, was invariably found. These ultrastructural findings became extensive at 28 days follow-up. Colloidal iron staining of kidney biopsies revealed loss of glomerular polyanions as early as 3 hours and very marked loss at 28 hours after adriamycin injection. Polyanions were totally absent at 13 days and were still undetectable at 28 days. Thus, the loss of polyanionic charges associated with the sialic acid coat precedes the ultrastructural changes and the onset of proteinuria. These changes appeared similar to those reported in rats treated with daunomycin or puromycin animonucleoside. The present study supports in a different animal model the concept that both morphologic changes and proteinuria are the consequence of a common primary event that is the loss of glomerular fixed negative charges.

Interaction between heparin and adriamycin in mice bearing the Lewis lung carcinoma.

The investigation was prompted by the observation that adriamycin can interact with heparin in vitro and reduces its anticoagulant activity in ex vivo tests in humans. The possible interactions between these two drugs were studied in C57Bl/6J mice bearing the Lewis Lung Carcinoma (3LL). The anticoagulant activity of heparin was temporarily reduced by concomitant treatment with adriamycin, as indicated by both activated partial thromboplastin times and blood recalcification times. In contrast, no changes were found in the kinetics of adriamycin disappearance from blood and accumulation in tissues if mice had been pretreated with heparin. Moreover, the effect of adriamycin on tumour and metastasis growth was unchanged by the association with the anticoagulant. These data indicate that the short-lived interaction between adriamycin and heparin, which can be documented by coagulation tests, does not necessarily involve a modification in the anticancer activity of the anthracycline.