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Prostacyclin and thromboxane in ovarian cancer: Effect of cytostatics and prostaglandin synthesis inhibitors
GYNECOLOGIC
ONCOLOGY
16, 340-345 (1983)
Prostacyclin and Thromboxane in Ovarian Cancer: Effect of Cytostatics and Prostaglandin Synthesis Inhibitors OLAVI YLIKORKALA, M.D.,*? ANTTI KAUPPILA, M.D.,t AND LASSE VIINIKKA, M.D.S Departments of Obstetrics and Gynecology, Universities of *Helsinki and fOula, and $Department of Clinical Chemistry, University of Oh, Finland Received June 8, 1982 The production of the antiaggregatory prostacyclin (PGl,) and proaggregatory thromboxane A, (TxA,) were studied in 19 patients with residual ovarian cancer. The plasma 6-keto-PGF,, (a metabolite of PGl,) in cancer patients (146.7 2 14.7 pg/ml, mean * SE) was higher (P < 0.02) than that in the controls (85.3 ? 9.2 pg/ml, n = 17). Also the releases of TxB, (a metabolite of TxA2) during spontaneous clotting of the blood samples were greater (P < 0.05) in the patients (253.4 -?r30.1 rig/ml) than controls (183.2 * 19.8 rig/ml). The combined administration of doxorubicin, cyclophosphamide and cis-platinum temporarily decreased the plasma 6-keto-PGF,, levels but caused no changes in TxB, generation. Prostaglandin synthesis inhibitors (acetylsalicyclic acid or indomethacin) during cytostatic infusion did not prevent the occurrence of the acute side effects of cytostatics, but they inhibited the TxB, generation. Thus our data suggest that residual ovarian cancer is accompanied by increased production of PGI, and TxA,, and that prostaglandins have no role in the acute side effects of cancer chemotherapy.
Much evidence suggests that various human cancer cells produce classic prostaglandins (PG) as thoroughly reviewed recently [l]. However, only few studies exist on the new PGs, antiaggregatory prostacyclin (PGIJ [2] and proaggregatory thromboxane A2 (TXA,) [3], in cancer patients [4-61. We designed this investigation to determine the following: i.
the basal production of PGlz and TxA, in patients with residual ovarian cancer; ii. the effect of cancer chemotherapy on PGl, and TxA, production; and ... 111. the effects of the treatments with PG synthesis inhibitors, acetylsalicylic acid, and indomethacin on PG12 and TxA, and on the occurrence of the side effects during cytostatic administration. PATIENTS AND METHODS
Nineteen patients with residual ovarian cancer admitted to hospital for l-6 treatments of cytostatics volunteered for this study after having been informed about its purpose and course. The approval from the local Committee of the 340 0090-8258/83 $1.50 Copyright All rights
0 1983 by Academic Press, Inc. of reproduction in any form reserved.
PROSTACYCLIN AND THROMBOXANE IN OVARIAN CANCER
341
Ethics was obtained. The women were between 49 and 73 years old (65.8 + 3.1 years, mean 2 SE). The sizes of the residual tumor, as assessed during pelvic examination, ranged from a mass of 2-3 cm to generalized peritoneal carsinomatosis. All patients had normal counts of white blood cells (3.0 x log/liter) and platelets (100 X log/liter) as well as normal concentrations of serum urea (<9 nmole/liter) and creatinine (cl20 nmole/liter) before treatment. The patients denied the use of drugs capable of interfering with the synthesis of PGs 10 days prior to treatment, but five women used digoxin, three used beta blockers, and one used thyroxine. Seventeen age-matched women, out of whom three used digoxin and two used beta blockers, were studied as controls. The patients were given doxorubicin (40 mg/m’) and cyclophosphamide (500 mg/m’) as separate slow intravenous infusions of 30-60 min starting at 9 AM. This infusion was complemented with cis-platinum diammine dichloride (50 mg/m’) given in two infusions of 4 hr each. During cytostatic administration, the patients received altogether 3000 ml of physiological saline and 200 ml of 20% mannitol. Ten patients were given metoclopramide and 13 patients dehydrobenzperidol to alleviate nausea and vomiting during the infusion. To study the effect of P6 synthesis inhibitors on the acute side effects of cytostatics, the patients were allocated at random to three groups. One group (n = 6) received 500 mg of acetylsalicylic acid (ASA) four times with 4-hr intervals starting at 8 AM on the treatment day. Another group was given a 50mg suppository of indomethacin three times with 6-hr intervals starting at 8 AM, whereas seven patients served as controls. The side effects were rated as suggested recently by Miller et al. [7] (nausea/vomiting: none = grade 0; nausea = grade 1; transient vomiting = grade 2; vomiting requiring therapy = grade 3; intractable vomiting = grade 4). Blood samples were collected at 8 AM on the day preceding, on the treatment day, and 3 and 8 hr after the onset of cytostatic administration, as well as at 8 AM on the first 3 post-treatment days. At every occasion, two samples were taken; one went into an ice-cold heparinized tube containing indomethacin (10 pmole/liter, final concentration) to get plasma for the measurement of 6-keto-prostaglandin F1, (dketo PGFI), a stable hydration product of PGl, [8], by radioimmunoassay [9] and the other went into a dry test tube and was allowed to clot at 37°C for 60 min to get serum for the measurement of thromboxane B2 (TxB,), a stable metabolite of TxA, [3], by radioimmunoassay [lo]. The amounts of TxB2 released during time- and temperature-controlled spontaneous clotting correlate closely (r > 0.9) with those released during induced aggreation in platelet-rich plasma [lo]. The paired an unpaired t tests were employed for testing the significance of the differences. RESULTS
Baseline Concentrations of 6-keto-PGF,, and TxB2 The plasma 6-keto-PGF,, concentrations in cancer patients were higher than those in the controls (Table 1). The tumor histology was not related to the plasma 6-keto-PGF,, concentrations because they did not differ between patients with serous cystadenocarcinoma (161.8 2 31.7 pg/ml, mean + SE, n = 7), unspecified
342
YLIKORKALA,
KAUPPILA,
AND
VIINIKKA
TABLE 1 THE CONCENTRATION (MEAN 2 SE) OF 6-VETO-PROSTAGLANDIN F,, AND THROMBOXANE B, IN PATIENTS WITH RESIDUAL OVARIAN CANCER BEFORE THE TREATMENT WITH CYTOSTATICS AS COMPARED WITH THE RESPECTIVE LEVELS IN THE CONTROLS Plasma Population Patients with residual ovarian cancer (n = 19) cytostatics alone (n = 7) cytostatics + ASA (n = 6) cytostatics + indomethacin (n = 6) Controls a P < 0.01 in comparison ’ P < 0.05 in comparison
6-keto-PGF,,
with with
146.7 154.5 128.2 155.7 85.3
f k IT k k
Serum
thromboxane
B,
(w/ml)
(pdml)
14.7 23.6 20.1b 34.5” 9.1
253.4’ 328.8 232.5 189.3 183.2
f 2 k + 2
30.1 25.0’ 69.0 35.1 17.8
the controls. the controls.
adenocarcinoma (147.1 + 18.0 pg/ml, II = 9), anaplastic carcinoma (99.5 & 3.7 pg/ml, n = 2), or mutinous cystadenocarcinoma (119 pg/ml, n = 1). The plasma 6-keto-PGF,, correlated with the erythrocyte sedimentation rate (r = 0.617, P < 0.01, n = 16) but not with the size of the residual tumor. The platelets capacity to produce TxB, was increased in cancer patients (Table l), but it was in no relation to the histology or size of the tumor. Effect of Cytostatics on 6-keto-PGF,, and TxB, The infusion of cytostatics was accompanied by decreases in plasma 6-ketoPGF,, concentrations in samples taken at 3 and 8 hr, whereas no changes were seen in serum TxB, (Fig. I). Effect of Prostaglandin Synthesis Inhibitors on 6-keto-PGF,, and TxB2 The use of ASA and indomethacin did not potentiate the effect of cytostatics on the plasma 6-keto-PGF,, concentrations (Fig. 1). Although both ASA and indomethacin inhibited the TxB, generation, the effect of ASA lasted much longer than did that of indomethacin (Fig. 1). Occurrence of Chemotherapy Side Effects All patients suffered from nausea, vomiting, and/or diarrhea during cytostatic infusion. Vomiting requiring other therapy than the study treatments occurred in four of six patients with ASA treatment, in three of six patients with indomethacin, and in six of seven patients without PG synthesis inhibitors. However, the mean scores for nausea and vomiting [7] in the ASA group (2.2, range l-3), indomethacin group (2.5, range l-4), and in patients treated with cytostatics alone (3.0, range l-4) did not differ. DISCUSSION
We present here evidence that PG12 generation, as measured by plasma 6keto-PGF,, levels, is increased in patients with residual ovarian cancer. The increased PGIZ production might originate from the ovarian cancer cells or be
PROSTACYCLIN
AND
THROMBOXANE
IN
A
3nRs
a
TIME
AFTER
~DAY
OVARIAN
CYTOSTATICI
n n
2
343
CANCER
ALONE +ASA
+ INDO
3
START OF TREATMENT
FIG. 1. The relative changes in plasma 6-keto-PGF,, and serum TxB, concentrations during the combined administration of three cytostatics (doxorubicin, cyclophosphamide, and cis-platinum) alone or together with acetylsahcyhc acid (ASA) or indomethacin (INDO). * = P < 0.05, ** = P < 0.01, and *** = P < 0.001 in comparison with the initial levels.
a result of a stimulation of vessel wall PG12 production by the tumor effects. The lacking correlation between the size of the residual tumor, as approximate during pelvic examination, and plasma 6-keto PGF,, does not support the theory of PG12 production by the cancer itself. It seems more likely that PGl, production increases as a paraneoplastic phenomenon, as suggestedby a dependence between plasma 6-keto-PGF,, and erythrocyte sedimentation rate. In view of the antiaggregatory effect of PGl, and the possible role of cancer cell-induced platelet aggregation in the metastasis formation [ll-131, the increased PGl, may be an attempt to prevent the metastatic spread of the ovarian cancer. This is supported by a recent report showing that exogenous injection of PG12reduced the number of metastatic melanoma cells in mice [ 141. We further demonstrate that the platelets’ capacity to generate TxB2 is increased in patients with ovarian cancer. It may be a primary paraneoplastic change or a compensatory phenomenon to the increased PG12, since a balance between PGlz and TxA, rather than either agent alone may determine the vascular wallplatelet interaction [15]. If the increase in TxA, production is a primary change,
344
YLIKORKALA,
KAUPPILA,
AND
VIINIKKA
it might provide one explanation for the increased occurrence of thromboembolic complication in patients with ovarian cancer. The combined administration of three cytostatics suppressed PGI, generation. This is in principal agreement with our earlier finding from patients with various gynecologic malignancies [4]. c&Platinum is hardly the agent responsible for this PGlz decrease, because plasma 6-keto-PGF,, levels were normal at 8 hr, when &-platinum was still given, and c&-platinum did not decreasePG12production in another study [5]. No conclusion about the effect of cyclophosphamide on PG12 production can be drawn on the basis of the present knowledge. It is, however, likely that doxorubicin was the agent responsible for decreased PG12 synthesis because it stimulates the formation of lipid peroxides [16,17], which are potent inhibitors of PGl, synthesis [ 181. The treatment with PG synthesis inhibitors failed to prevent nausea, vomiting, and/or diarrhea during cytostatic administration. This result together with two reports showing no release of classic PGs during cytostatic infusion [4,5] disputes the role of PGs as a reason for the acute side effects of cancer chemotherapy [I]. Furthermore, ASA and indomethacin treatments caused no inhibition in PGl, synthesis in vivo, but they suppressed almost totally the TxA2 generation. Keeping in mind the role of platelet aggregation in metastasisformation and the antimetastatic activity of PGlz [14], this finding may explain the anticancer effect of PG synthesis inhibitors in mice [I ,19,20] although the role of PGs in this action has been disputed [21]. The various recovery of TxA2 production after ASA and indomethacin treatment is compatible with the irreversible inactivation of platelet cyclooxygenase by ASA and reversible inactivation by indomethacin [22,23]. ACKNOWLEDGMENTS This study was supported by the Medical Research Council, the Academy of Finland, and by the Finnish Cancer Research Institute.
REFERENCES 1. Bennet, A. Prostaglandins and cancer, in Practical applications of prostaglandins and their synthesis inhibitors (S. M. M. Karim, Ed.), pp. 149-188, Maple Press, York Pa. (1979). 2. Moncada, S., Gryglewski, R., Bunting, S., and Vane, J. R. An enzyme isolated from arteries transforms prostaghmdin endoperoxide to an unstable substance that inhibits platelet aggregation, Nature
(London)
263, 663-665 (1976).
3. Hamberg, M., Svensson, J., and Samuelsson, B. Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides, Proc. Natl. Acad. Sci. USA 72, 2994-8, (1975). 4. Ylikorkala, O., Kauppila, A., and Viinikka, L. Effect of cytostatics ofprostaglandin FZo,prostacyclin, and thromboxane in patients with gynecologic malignancies, Obstet. Gynecol. 58, 483-486 (1981). 5. Curry, S. L., Rine, J., Whitney, C. W., Nahhas, W. A., Mortel, R., and Demers, L. M. The role of prostaglandins in the excessive nausea and vomiting after intravenous cis-platinum therapy, Gynecol. Oncol. 12, 89-91 (1981). 6. Khan, O., Hensby, C. N., and Williams, G. Prostacyclin in prostatic diseases, in Clinical pharmacology ofprostacyclin (P. J. Lewis, and J. O’Grady, Eds.), Raven Press, New York, pp. 49-52 (1981). 7. Miller, A. B., Hoogstraten, B., Staquet, M., and Winkler, A. Reporting results of cancer treatment, Cancer 47, 207-214 (1981).
PROSTACYCLIN
AND
THROMBOXANE
IN
OVARIAN
CANCER
345
8. Johnson, R. A., Morton, D. R., Khmer, J. H., Gorman, R. R., McGuire, J. C., Sun, F. F., Whittaker, N., Bunting, S., Salmon, J., Moncada, S., and Vane, J. R. The chemical structure of prostaglandin X (prostacyclin), Prostaglandins 12, 915-926 (1976). 9. Ylikorkala, O., Kaila, J., and Viinikka, L. Prostacyclin and thromboxane in diabetes, Brit. Med. J. 283, 1148-1150 (1981). 10. Viinikka, L., and Ylikorkala, 0. Measurement of thromboxane B2 in human plasma or serum by radioimmunoassay, Prostaglandins 20, 759-766 (1980). 11. Marcum, J. M., McGill, M., Bastida, E., Ordinas, A., and Jamieson, G. A. The interaction of platelets, tumor cells, and vascular subendothelium, J. Lab. C/in. Med. 96, 1046-1053 (1980). 12. Gasic, G. U., Gasic, T. B., Galanti, N., Johnson, T., and Murphy, S. Platelet-tumor cell interaction in mice: The role of platelets in the spread of malignant disease, Int. J. Cancer. 11, 704-709 (1973). 13. Bastida, E., Ordinas, A., and Jamieson, G. A. Idiosyncratic platelet responses to human tumour cells, Nature (London) 291, 661-662 (1981). 14. Honn, K. V., Cicone, B., and Skoff, A. Prostacyclin: A potent antimetastatic agent, Science 212, 1270-1272 (1981). 15. Moncada, S., and Vane, J. R. Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls, N. Engl. J. Med. 300, 1142-1147 (1979). 16. Myers, C. E., McGuire, W. P., Liss, R. H., Grotzinger, K., and Young, R. C. Adriamycin: The role of lipid peroxidation in cardiac toxicity and tumor response, Science 197, 165-167 (1977). 17. Myers, C. E., McGuire, W., and Young, R. Adriamycin: Amelioration of toxicity by cy-tocopherol, Cancer Treat. Rep. 60, 961-962 (1976). 18. Moncada, S., Higgs, E. A., and Vane, J. R. Human arterial venous tissues generate prostacyclin (prostaglandin X), a potent inhibitor of platelet aggregation, Lancer 1, 18-21 (1977). 19. Lynch, N. R., Castes, M., Astoin, M., and Salomon, .I. C. Mechanism of inhibition of tumour growth by aspirin and indomethacin, Brit. .Z. Cancer 38, 509-517 (1978). 20. Berstock, D. A., Houghton, J., and Bennet, A. Improved anticancer effect by combining cytotoxic drugs with an inhibitor or prostaglandin synthesis, Cancer Treat. Rev. 6, 69-71 (1979). 21. deMello, M. C. F., Bayer, B. M., and Beaven, M. A. Evidence that prostaglandins do not have a role in the cytostatic action of anti-inflammatory drugs, Eiochem. Pharmacol. 29, 311-318 (1980). 22. Burch, J. W., Stanford, N., and Majerus, P. W. Inhibition of platelet prostaglandin synthetase by oral aspirin, C/in. Invest. 61, 314-319 (1978). 23. Burch, J. W., and Majerus, P. W. The role of prostaglandins in platelet function, Semin. Hematol. 16, 196-207 (1979).
ONCOLOGY
16, 340-345 (1983)
Prostacyclin and Thromboxane in Ovarian Cancer: Effect of Cytostatics and Prostaglandin Synthesis Inhibitors OLAVI YLIKORKALA, M.D.,*? ANTTI KAUPPILA, M.D.,t AND LASSE VIINIKKA, M.D.S Departments of Obstetrics and Gynecology, Universities of *Helsinki and fOula, and $Department of Clinical Chemistry, University of Oh, Finland Received June 8, 1982 The production of the antiaggregatory prostacyclin (PGl,) and proaggregatory thromboxane A, (TxA,) were studied in 19 patients with residual ovarian cancer. The plasma 6-keto-PGF,, (a metabolite of PGl,) in cancer patients (146.7 2 14.7 pg/ml, mean * SE) was higher (P < 0.02) than that in the controls (85.3 ? 9.2 pg/ml, n = 17). Also the releases of TxB, (a metabolite of TxA2) during spontaneous clotting of the blood samples were greater (P < 0.05) in the patients (253.4 -?r30.1 rig/ml) than controls (183.2 * 19.8 rig/ml). The combined administration of doxorubicin, cyclophosphamide and cis-platinum temporarily decreased the plasma 6-keto-PGF,, levels but caused no changes in TxB, generation. Prostaglandin synthesis inhibitors (acetylsalicyclic acid or indomethacin) during cytostatic infusion did not prevent the occurrence of the acute side effects of cytostatics, but they inhibited the TxB, generation. Thus our data suggest that residual ovarian cancer is accompanied by increased production of PGI, and TxA,, and that prostaglandins have no role in the acute side effects of cancer chemotherapy.
Much evidence suggests that various human cancer cells produce classic prostaglandins (PG) as thoroughly reviewed recently [l]. However, only few studies exist on the new PGs, antiaggregatory prostacyclin (PGIJ [2] and proaggregatory thromboxane A2 (TXA,) [3], in cancer patients [4-61. We designed this investigation to determine the following: i.
the basal production of PGlz and TxA, in patients with residual ovarian cancer; ii. the effect of cancer chemotherapy on PGl, and TxA, production; and ... 111. the effects of the treatments with PG synthesis inhibitors, acetylsalicylic acid, and indomethacin on PG12 and TxA, and on the occurrence of the side effects during cytostatic administration. PATIENTS AND METHODS
Nineteen patients with residual ovarian cancer admitted to hospital for l-6 treatments of cytostatics volunteered for this study after having been informed about its purpose and course. The approval from the local Committee of the 340 0090-8258/83 $1.50 Copyright All rights
0 1983 by Academic Press, Inc. of reproduction in any form reserved.
PROSTACYCLIN AND THROMBOXANE IN OVARIAN CANCER
341
Ethics was obtained. The women were between 49 and 73 years old (65.8 + 3.1 years, mean 2 SE). The sizes of the residual tumor, as assessed during pelvic examination, ranged from a mass of 2-3 cm to generalized peritoneal carsinomatosis. All patients had normal counts of white blood cells (3.0 x log/liter) and platelets (100 X log/liter) as well as normal concentrations of serum urea (<9 nmole/liter) and creatinine (cl20 nmole/liter) before treatment. The patients denied the use of drugs capable of interfering with the synthesis of PGs 10 days prior to treatment, but five women used digoxin, three used beta blockers, and one used thyroxine. Seventeen age-matched women, out of whom three used digoxin and two used beta blockers, were studied as controls. The patients were given doxorubicin (40 mg/m’) and cyclophosphamide (500 mg/m’) as separate slow intravenous infusions of 30-60 min starting at 9 AM. This infusion was complemented with cis-platinum diammine dichloride (50 mg/m’) given in two infusions of 4 hr each. During cytostatic administration, the patients received altogether 3000 ml of physiological saline and 200 ml of 20% mannitol. Ten patients were given metoclopramide and 13 patients dehydrobenzperidol to alleviate nausea and vomiting during the infusion. To study the effect of P6 synthesis inhibitors on the acute side effects of cytostatics, the patients were allocated at random to three groups. One group (n = 6) received 500 mg of acetylsalicylic acid (ASA) four times with 4-hr intervals starting at 8 AM on the treatment day. Another group was given a 50mg suppository of indomethacin three times with 6-hr intervals starting at 8 AM, whereas seven patients served as controls. The side effects were rated as suggested recently by Miller et al. [7] (nausea/vomiting: none = grade 0; nausea = grade 1; transient vomiting = grade 2; vomiting requiring therapy = grade 3; intractable vomiting = grade 4). Blood samples were collected at 8 AM on the day preceding, on the treatment day, and 3 and 8 hr after the onset of cytostatic administration, as well as at 8 AM on the first 3 post-treatment days. At every occasion, two samples were taken; one went into an ice-cold heparinized tube containing indomethacin (10 pmole/liter, final concentration) to get plasma for the measurement of 6-keto-prostaglandin F1, (dketo PGFI), a stable hydration product of PGl, [8], by radioimmunoassay [9] and the other went into a dry test tube and was allowed to clot at 37°C for 60 min to get serum for the measurement of thromboxane B2 (TxB,), a stable metabolite of TxA, [3], by radioimmunoassay [lo]. The amounts of TxB2 released during time- and temperature-controlled spontaneous clotting correlate closely (r > 0.9) with those released during induced aggreation in platelet-rich plasma [lo]. The paired an unpaired t tests were employed for testing the significance of the differences. RESULTS
Baseline Concentrations of 6-keto-PGF,, and TxB2 The plasma 6-keto-PGF,, concentrations in cancer patients were higher than those in the controls (Table 1). The tumor histology was not related to the plasma 6-keto-PGF,, concentrations because they did not differ between patients with serous cystadenocarcinoma (161.8 2 31.7 pg/ml, mean + SE, n = 7), unspecified
342
YLIKORKALA,
KAUPPILA,
AND
VIINIKKA
TABLE 1 THE CONCENTRATION (MEAN 2 SE) OF 6-VETO-PROSTAGLANDIN F,, AND THROMBOXANE B, IN PATIENTS WITH RESIDUAL OVARIAN CANCER BEFORE THE TREATMENT WITH CYTOSTATICS AS COMPARED WITH THE RESPECTIVE LEVELS IN THE CONTROLS Plasma Population Patients with residual ovarian cancer (n = 19) cytostatics alone (n = 7) cytostatics + ASA (n = 6) cytostatics + indomethacin (n = 6) Controls a P < 0.01 in comparison ’ P < 0.05 in comparison
6-keto-PGF,,
with with
146.7 154.5 128.2 155.7 85.3
f k IT k k
Serum
thromboxane
B,
(w/ml)
(pdml)
14.7 23.6 20.1b 34.5” 9.1
253.4’ 328.8 232.5 189.3 183.2
f 2 k + 2
30.1 25.0’ 69.0 35.1 17.8
the controls. the controls.
adenocarcinoma (147.1 + 18.0 pg/ml, II = 9), anaplastic carcinoma (99.5 & 3.7 pg/ml, n = 2), or mutinous cystadenocarcinoma (119 pg/ml, n = 1). The plasma 6-keto-PGF,, correlated with the erythrocyte sedimentation rate (r = 0.617, P < 0.01, n = 16) but not with the size of the residual tumor. The platelets capacity to produce TxB, was increased in cancer patients (Table l), but it was in no relation to the histology or size of the tumor. Effect of Cytostatics on 6-keto-PGF,, and TxB, The infusion of cytostatics was accompanied by decreases in plasma 6-ketoPGF,, concentrations in samples taken at 3 and 8 hr, whereas no changes were seen in serum TxB, (Fig. I). Effect of Prostaglandin Synthesis Inhibitors on 6-keto-PGF,, and TxB2 The use of ASA and indomethacin did not potentiate the effect of cytostatics on the plasma 6-keto-PGF,, concentrations (Fig. 1). Although both ASA and indomethacin inhibited the TxB, generation, the effect of ASA lasted much longer than did that of indomethacin (Fig. 1). Occurrence of Chemotherapy Side Effects All patients suffered from nausea, vomiting, and/or diarrhea during cytostatic infusion. Vomiting requiring other therapy than the study treatments occurred in four of six patients with ASA treatment, in three of six patients with indomethacin, and in six of seven patients without PG synthesis inhibitors. However, the mean scores for nausea and vomiting [7] in the ASA group (2.2, range l-3), indomethacin group (2.5, range l-4), and in patients treated with cytostatics alone (3.0, range l-4) did not differ. DISCUSSION
We present here evidence that PG12 generation, as measured by plasma 6keto-PGF,, levels, is increased in patients with residual ovarian cancer. The increased PGIZ production might originate from the ovarian cancer cells or be
PROSTACYCLIN
AND
THROMBOXANE
IN
A
3nRs
a
TIME
AFTER
~DAY
OVARIAN
CYTOSTATICI
n n
2
343
CANCER
ALONE +ASA
+ INDO
3
START OF TREATMENT
FIG. 1. The relative changes in plasma 6-keto-PGF,, and serum TxB, concentrations during the combined administration of three cytostatics (doxorubicin, cyclophosphamide, and cis-platinum) alone or together with acetylsahcyhc acid (ASA) or indomethacin (INDO). * = P < 0.05, ** = P < 0.01, and *** = P < 0.001 in comparison with the initial levels.
a result of a stimulation of vessel wall PG12 production by the tumor effects. The lacking correlation between the size of the residual tumor, as approximate during pelvic examination, and plasma 6-keto PGF,, does not support the theory of PG12 production by the cancer itself. It seems more likely that PGl, production increases as a paraneoplastic phenomenon, as suggestedby a dependence between plasma 6-keto-PGF,, and erythrocyte sedimentation rate. In view of the antiaggregatory effect of PGl, and the possible role of cancer cell-induced platelet aggregation in the metastasis formation [ll-131, the increased PGl, may be an attempt to prevent the metastatic spread of the ovarian cancer. This is supported by a recent report showing that exogenous injection of PG12reduced the number of metastatic melanoma cells in mice [ 141. We further demonstrate that the platelets’ capacity to generate TxB2 is increased in patients with ovarian cancer. It may be a primary paraneoplastic change or a compensatory phenomenon to the increased PG12, since a balance between PGlz and TxA, rather than either agent alone may determine the vascular wallplatelet interaction [15]. If the increase in TxA, production is a primary change,
344
YLIKORKALA,
KAUPPILA,
AND
VIINIKKA
it might provide one explanation for the increased occurrence of thromboembolic complication in patients with ovarian cancer. The combined administration of three cytostatics suppressed PGI, generation. This is in principal agreement with our earlier finding from patients with various gynecologic malignancies [4]. c&Platinum is hardly the agent responsible for this PGlz decrease, because plasma 6-keto-PGF,, levels were normal at 8 hr, when &-platinum was still given, and c&-platinum did not decreasePG12production in another study [5]. No conclusion about the effect of cyclophosphamide on PG12 production can be drawn on the basis of the present knowledge. It is, however, likely that doxorubicin was the agent responsible for decreased PG12 synthesis because it stimulates the formation of lipid peroxides [16,17], which are potent inhibitors of PGl, synthesis [ 181. The treatment with PG synthesis inhibitors failed to prevent nausea, vomiting, and/or diarrhea during cytostatic administration. This result together with two reports showing no release of classic PGs during cytostatic infusion [4,5] disputes the role of PGs as a reason for the acute side effects of cancer chemotherapy [I]. Furthermore, ASA and indomethacin treatments caused no inhibition in PGl, synthesis in vivo, but they suppressed almost totally the TxA2 generation. Keeping in mind the role of platelet aggregation in metastasisformation and the antimetastatic activity of PGlz [14], this finding may explain the anticancer effect of PG synthesis inhibitors in mice [I ,19,20] although the role of PGs in this action has been disputed [21]. The various recovery of TxA2 production after ASA and indomethacin treatment is compatible with the irreversible inactivation of platelet cyclooxygenase by ASA and reversible inactivation by indomethacin [22,23]. ACKNOWLEDGMENTS This study was supported by the Medical Research Council, the Academy of Finland, and by the Finnish Cancer Research Institute.
REFERENCES 1. Bennet, A. Prostaglandins and cancer, in Practical applications of prostaglandins and their synthesis inhibitors (S. M. M. Karim, Ed.), pp. 149-188, Maple Press, York Pa. (1979). 2. Moncada, S., Gryglewski, R., Bunting, S., and Vane, J. R. An enzyme isolated from arteries transforms prostaghmdin endoperoxide to an unstable substance that inhibits platelet aggregation, Nature
(London)
263, 663-665 (1976).
3. Hamberg, M., Svensson, J., and Samuelsson, B. Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides, Proc. Natl. Acad. Sci. USA 72, 2994-8, (1975). 4. Ylikorkala, O., Kauppila, A., and Viinikka, L. Effect of cytostatics ofprostaglandin FZo,prostacyclin, and thromboxane in patients with gynecologic malignancies, Obstet. Gynecol. 58, 483-486 (1981). 5. Curry, S. L., Rine, J., Whitney, C. W., Nahhas, W. A., Mortel, R., and Demers, L. M. The role of prostaglandins in the excessive nausea and vomiting after intravenous cis-platinum therapy, Gynecol. Oncol. 12, 89-91 (1981). 6. Khan, O., Hensby, C. N., and Williams, G. Prostacyclin in prostatic diseases, in Clinical pharmacology ofprostacyclin (P. J. Lewis, and J. O’Grady, Eds.), Raven Press, New York, pp. 49-52 (1981). 7. Miller, A. B., Hoogstraten, B., Staquet, M., and Winkler, A. Reporting results of cancer treatment, Cancer 47, 207-214 (1981).
PROSTACYCLIN
AND
THROMBOXANE
IN
OVARIAN
CANCER
345
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