The Journal of International Medical Research Endovascular 2000; 28: Embolization 313 317 of Effects of Cancer Chemotherapy on the Blood Fibrinogen Concentrations of Cancer Patients D-Y LU 1, X-L CHEN 2, J-Y CAO 1, Z LI 2, H-W XUE 2, L-J LUO 2 AND B XU 3 1 School of Life Sciences, Shanghai University, Shanghai, People s Republic of China; 2 Central Hospital of Jing-An District, Shanghai 200040, People s Republic of China; 3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People s Republic of China Blood fibrinogen concentrations and glutamic pyruvic transaminase activities of 66 adult cancer in (aged 22 70 years) were determined both before and after one or two chemotherapy regimens. The percentage of hepatoma with abnormal blood fibrinogen levels (< 1.5 or > 6.0 g/l) was higher (64.3% of 14 ) than that in other cancer categories (19.2% of 52 ). The mean blood fibrinogen concentrations of male (3.5 g/l) and female (4.5 g/l) cancer were higher than those previously reported for healthy humans (2.8 and 2.9 g/l, respectively). After chemotherapy, blood fibrinogen concentrations decreased in whose primary tumours were surgically removed (from 4.8 to 3.2 g/l) but increased (from 3.0 to 4.8 g/l) in those who did not undergo surgery. Glutamic pyruvic transaminase activities did not appear to be related to blood fibrinogen levels. We conclude that the increase in mean blood fibrinogen levels of cancer is probably related to tumour growth. Different mechanisms may operate in with hepatoma. KEY WORDS: FIBRINOGEN; BLOOD FIBRINOGEN CONCENTRATION; CANCER CHEMOTHERAPY; TUMOUR PATHOGENESIS 313
D-Y Lu, X-L Chen, J-Y Cao INTRODUCTION The relationship between fibrinogen or fibrin concentrations within the body and solid tumours is of continuing interest to experimental biologists and clinical oncologists. 1 Experimental data suggest that there are three possible ways in which fibrinogen or fibrin may be involved in tumour growth and metastasis: (i) it may form a scaffold to which tumour cells can attach as tumour stroma; (ii) it may form a tumour cocoon to shield tumour cells from attack by activated lymphocytes; (iii) it may help angiogenesis in tumour tissues. 2,3 Blood fibrinogen, a precursor of fibrinogen and fibrin in tumours, was found to be increased in mice bearing solid tumours, 4 and some antitumour drugs, such as L-4-oxalysine, 5 have been found, in experimental models, to inhibit the blood fibrinogen levels of mice bearing solid tumours. Whether there are differences in blood fibrinogen concentrations between healthy individuals and cancer in clinics has not been assessed clinically. It has, however, been suggested that some antineoplastic drugs, other than anticoagulants, may affect tumour metastasis via the fibrinogen pathway. 6,7 An understanding of the relative fibrinogen levels of healthy individuals and cancer might also be useful in the development of prognostic forecasting and might assist the selection of appropriate chemotherapy regimens. We therefore collected clinical data on fibrin levels in cancer and compared them with those of healthy individuals. PATIENTS AND METHODS In (aged 22 70 years), diagnosed (by pathological or B-ultrasonic wave evaluation) as having late-stage cancers of various origins were enrolled. Blood fibrinogen contents and glutamic pyruvic transaminase (GPT) activities were determined by routine methods both before treatment and after one or two conventional chemotherapy regimens (drugs including camptothecin, cisplatin, carboxyplatin, adriamycin, bleomycin, arabinosyl cytosine or VP16, etc, in single or combined protocols). Blood (3 ml) was anticoagulated with sodium citrate. After centrifugation at 2000 g for 10 min, 0.5 ml of plasma was taken and fibrinogen was precipitated by calcium salt. The fibrinogen was dissolved in sodium hydroxide solution and was assayed using the method of Lowry 8 The data were compared using Student s t-test. We also collected the corresponding data from who had been admitted to the hospital with non-cancer conditions. RESULTS Fifty male and 50 female in (aged 18 55 years) with non-cancer conditions were included in the statistical analysis. In the cancer-patient group, totals of 34 male and 32 female were included. They had a diverse range of cancers, including cancer of the lung, stomach, liver, colon, mammary cancer, etc. Treatment regimes were likewise diverse and varied according to the origin of cancer. The initial mean blood fibrinogen concentrations of these were 3.48 g/l and 4.47 g/l, respectively. Of the 14 with hepatoma, nine (64.3%) had abnormal blood fibrinogen concentrations (< 1.5 g/l or > 6 g/l): in six the concentrations were < 1.5 g/l and in three they were > 6 g/l. Among the other 52, the proportion of with abnormal fibrinogen concentrations was 19.2%, similar to that found among otherwise healthy humans (20%). Patients who had tolerated a complete chemotherapy regimen (n = 33) showed a slight decrease in blood fibrinogen levels after chemotherapy, 314
D-Y Lu, X-L Chen, J-Y Cao from 3.99 to 3.58 g/l (P = 0.213). Fifteen who had not undergone operations showed an increase of blood fibrinogen concentrations from 2.99 to 4.82 g/l (P = 0.026). Eighteen whose tumours had been removed by operations showed a decrease in blood fibrinogen levels (from 4.82 to 3.15 g/l; P = 0.048). No discernible correlation between blood fibrinogen levels and GPT activity was found. DISCUSSION In the present study the mean blood fibrinogen levels in cancer were 3.48 and 4.47 g/l in males and females, respectively, compared with 2.76 and 2.90 g/l, respectively, in healthy adults. 9 This escalation of blood fibrinogen levels may result from enhancement of the synthesis of fibrinogen or from inhibition of its decomposition. The first mechanism is likely to result from genetic changes in the themselves, so we considered the genetic status of fibrinogen biosynthesis in the. According to Southan, 9 abnormal blood fibrinogen concentrations, both low (< 1.5 g/l) and high (> 6 g/l) concentrations, 10 are linked to genetic fibrinogen synthesis status, 8 and his data indicate that the frequency of abnormal fibrinogen concentrations among healthy people is 20%. In the present study, we found that abnormal blood fibrinogen concentrations occurred in 19.2% of cancer, apart from those with hepatoma, a frequency very similar to that found in healthy individuals. We deduced that the increased mean blood fibrinogen levels seen in cancer do not result from increases in the production of fibrinogen in, but are more likely to be attributable to tumour growth. This deduction was further supported by the finding that the blood fibrinogen concentrations of whose tumours were removed by operation was reduced, while the blood fibrinogen concentrations of who did not undergo surgery was increased. It appears that the escalation of fibrinogen is related to the presence of the tumour rather than being a characteristic of the themselves. It is thus possible that tumours produce factors that hinder the speed of degradation or cross-linking of fibrinogen in blood and that also affect the transformation of fibrinogen into fibrin in tumours (the activity of antithrombin, etc). 6 This is why many (two-thirds of all cancer ) have higher than normal blood fibrinogen levels but have common fibrinogen levels in tumour tissues. 3,11,12 Since the liver is the primary source of fibrinogen synthesis in the body (liver mesenchyme produces fibrinogen), it is not surprising that with hepatoma are more likely to show enhanced blood fibrinogen levels than with other tumour types. The present results indicate that the blood fibrinogen levels of are hardly influenced by chemotherapy if the tumour is not surgically removed. Some chemotherapy drugs, other than anticoagulants, reduced both blood fibrinogen levels and cancer metastasis in whose tumours were removed. We have previously found that antitumour drugs can affect the relationship between tumour and fibrinogen in vitro. 6,7 There are two possible explanations: (i) that the inhibition of tumour growth reduces the blood fibrinogen levels; (ii) that the drugs reduce the blood fibrinogen levels directly as in vitro. Fibrinogen itself can inhibit cytotoxic lymphocytes from attacking tumour cells, 2,3,13,14 and lower fibrinogen concentrations in the body can increase the defensive effects of the immune system and inhibit tumour growth. This mechanism 315
D-Y Lu, X-L Chen, J-Y Cao is considered to be among those by which many antitumour drugs can promote the survival of cancer. 6,7 ACKNOWLEDGEMENT This work was supported by grants from the Science and Technology Foundation of Shanghai High Education (No. 97A49). REFERENCES 1 Zacharski LR: Anticoagulation in the treatment of cancer in man. In: Malignancy and Hemostatic System (Donati MB, Davidson J, Garattini S, eds). New York: Raven Press, 1981; pp113 128. 2 Dvorak HF, Senger DR, Dvorak AM: Fibrin as a component of the tumor stroma: origins and biological significance. Cancer Metastasis Rev 1983; 2: 41 73. 3 Costantini V, Zacharski LR: The role of fibrin in tumor metastasis. Cancer Metastasis Rev 1992; 11: 283 290. 4 Poggi A, Polentarutti N, Donati MB, et al: Blood coagulation changes in mice bearing Lewis lung carcinoma, a metastasizing tumor. Cancer Res 1977; 37: 272 277. 5 Yue XF, Wu FG, Xu B: Effect of oxalysine on plasma fibrinogen content in tumorbearing mice. Acta Pharmacologica Sinica 1982; 3: 124 128. 6 Lu DY, Cao JY, Huang YP, et al: Comparison of some antineoplastic drugs on inhibiting thrombin catalizing fibrinogen clotting in vitro. Chin Med J (Engl) 1999: 112: 1052 1053. 7 Lu DY, Zhou PQ, Xu B: Homoharringtonine and razoxane reduce the binding of 125 I-fibrinogen to leukemia P388 and HL60 cells. Acta Pharmacologica Sinica 1995; 16: 187. 8 Lowry OH, Rosebrough NJ, Farr AL, et al: Protein measurement with the Folinphenol reagent. J Biol Chem 1953; 193: 265 275. 9 Southan C: Molecular and genetic abnormalities of fibrinogen. In: Fibrin, Fibrin Stabilisation and Fibrinolysis (Francis JL, ed). Chichester: Ellis Horwood Ltd, 1988; pp65 99. 10 Fried K, Kaufman S: Congenital afibrinogenaemia in 10 offspring of uncle niece marriage. Clin Genet 1980; 17: 223 227. 11 Wojtukiewicz MZ, Zacharski LR, Memoli VA, et al: Fibrin formation on vessel walls in hyperplastic and malignant prostate tissue. Cancer 1991; 67: 1377 1383. 12 Zacharski LR, Henderson WG, Rickles FR, et al: Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of the VA cooperative study 75. Cancer 1984; 53: 2046 2052. 13 Gunji Y, Gorelik E: Role of fibrin coagulation in protection of murine tumor cells from destruction by cytotoxic cell. Cancer Res 1988: 48: 5216 5221. 14 Cardinali M, Uchino R, Chung SI: Interaction of fibrinogen with murine melanoma cells: covalent association 316
D-Y Lu, X-L Chen, J-Y Cao with cell membrane and protection against recognition by lymphokineactivated killer cells. Cancer Res 1990; 50: 8010 8016. D-Y Lu, X-L Chen, J-Y Cao, Z Li, H-W Xue, L-J Luo and B Xu Effects of Cancer Chemotherapy on the Blood Fibrinogen Concentrations of Cancer Patients The Journal of International Medical Research 2000; 28: 313 317 Received for publication 17 April 2000 Accepted 25 April 2000 Copyright 2000 Cambridge Medical Publications Address for correspondence DR D-Y Lu School of Life Sciences, Shanghai University, Shanghai 200436, People s Republic of China. 317