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Larynx cancer and prostaglandins
Am J Otolaryngol 11:81-84,
1990
Larynx Cancer and Prostaglandins Z~YA CENIK, MD, AYSE CENIK, AND YAVUZ UYAR, MD
Prostaglandin levels in serum, tumor specimens, and normal larynx mucosa were measured before and after laryngectomy in 43 patients with larynx cancer. Related findings described elsewhere in the literature are discussed. AM J OTOLARYNGOL 11:81-84. 01990 by W.B. Saunders Company. Key words: larynx cancer, laryngeal mucosa, prostaglandin levels.
MATERIALS AND METHODS
The etiology of larynx cancer, despite its importance among malignant tumors of head and neck origin, has yet to be clarified. The action of some carcinogenic factors is accepted. The most important of these are smoking, alcohol, and chronic irritation. Larynx cancer occurs predominately in males, suggesting the possibility of a normal effect in its causation. Until now, a normal contribution to the etiology of larynx cancer has not been demonstrated. Prostaglandins (PGs) are accepted as local tissue hormones and known to have different physiologic effects. High prostaglandin levels have been measured in malignant tumors of different systems, and their study has caused new concepts to arise concerning cancer etiopathogenesis.l-I4 As tumor growth progressed, it was understood that PGs were synthesized more than normal due to changing tissue biochemistry, so that they were thought to act as a cocarcinogen in the development of malignant tumors.‘5S17 Studies investigating the levels of PGs in the malignant tumors of different systems in human beings have been reported. However, we could find no studies concerning the relationship between larynx cancer and PGs in our review of the literature. Therefore, we undertook, in this study, to measure the levels of PG in sera, tumor tissues and normal larynx mucosa before and after laryngectomy in larynx cancer patients receiving no prior treatment.
Forty-three patients with complaints of hoarseness, air obstruction, and the sensation of obstruction when swallowing were diagnosed as having larynx cancer by laryngoscopic and histopathologic examination, and were entered into our study. Prior to laryngectomy, all patients underwent blood, urea, electrocardiographic, chest x-ray and tests to rule out systemic disorders. All 43 patients were male and all smoked more than 20 cigarettes a day for a long period. The youngest patient was 38 years of age; the oldest was 72. The range of the age is shown in Table 1. Tumor location and stage are shown in Tables 2 through 4. Before laryngectomy, a 4-mL venous blood sample was taken from each patient in a sterile tube with heparm. To determine PG level, the plasma of the samples was separated and kept in closed tubes at -20%. On the 10th day after laryngectomy, 4mL venous blood samples were again taken and processed as before. Twenty subjects without inflammation or tumors comprised the control group. Peripheral venous samples were drawn from the control group, and PG levels evaluated. A bioassay method was used to measure PGs in tissue extractions and plasma samples. Since the mause gastric fundal muscle used in such as; PGE, PGF; the re-
sults obtained were called PG-like activity (PGBA). Student’s t test was applied in the statistical evaluation of the findings. Extraction and bioassay measurements were taken in the Pharmacology and Toxicology Institute of the Medical Faculty of Hacettepe University.
RESULTS The maximum level of serum PGBA obtained in the 43 patients with larynx cancer before laryngectomy was 126 ng/mL; the minimum level was 18 ng/mL, and the approximate serum level was 57. 6 + 4.0 ng/mL. After the operation, a reduction was observed in serum PGBA value. On the 16th postoperative day, the level of serum PGBA was 37.0 ? 4.0 ng/ mL. In the 20 subjects forming our control group, the maximum serum PGBA was 2 ng/mL. The ap-
Received June 1, 1989, from the Departments of Otolaryngology and Pharmacologv, School of Medicine. Ankara and fiacettepe University, Ankara, Turkey. Accepted for publication July 28, 1989. Address reprint requests to Ziya Cenik, MD, Seyh Sadrettin Mahallesi Turgutoglu Sokak, Dural Apartmani no. 1315 Konya, Turkey. 0 1990 by W.B. Saunders Company. 0196-0709/90/1102-0005$5.00/O
81
82
LARYNX CANCER AND PROSTAGLANDINS
TABLE 3. Glottic Cancers According to TNM System
TABLE 1. Age Distribution of the Patients
GLOTTIC STAGE
NO.OF~ATIENTS
AGE O-10
11-20 21-30 31-40 41-50 51-60 61-70 71-80
2 9 21 10 1
Total
43
Tl T, T, T,
DISCUSSION It has been proven that PGs are present in all tissues.” They exert a regulatory effect on various systems such as the urinary, cardiovascular, and especially the reproductive system.*-3,5-7,15*18,1g It is understood that PGs have effects other than those related to tumor growth.20*24Their effects on the proliferation of malignant cells and on tumor progress have been the most important areas of study. Prostaglandins were first detected in human malignant tumors in thyroid cancer by Williams et al in 1968.25 Bennet and colleagues26-28 reported that PG levels in tumor tissue were higher than in normal tissues and that PGs played a role in tumor progression. The levels of PGs in human tumor have been investigated by a number of investigators.
TI T, T, T*
Total
2 -
N, 3 5 4 -
N, 3 5 1
N,
N,
TOTAL
2 1
1 2 1 -
3 3 -
1
3 6 4 -
-
N, 2 1
14
Most of these studies concern thyroid, breast, and genital cancers.5**1*2g*30 Recently, increased levels of PG, especially of PGE,, have been reported in the tumor tissues of patients with head and neck carcinoma.31p32 Panje, 33 Balch et a1,34 Hirch et a1.35 suggested that PGE, may play a role in the inhibition of cellmediated immunity in head and neck cancer patients. In the 43 larynx cancer patients we examined, the level of PGBA was approximately 417.1 + 33.8rig/g..The average level of PGBA in the same patients was 153.8 rig/gin normal larynx mucosa samples. The difference between these levels is statistically significant (P < .OOl), and it shows that the level of PGs is high in larynx cancers, as it is in other malignant tumors (Fig 2). In our study, we tried to determine whether a relationship exists between the levels of PGBA and the histologic differentiation of the tumor. In three patients with undifferentiated squamous cell cancer, the level of PGBA was 240.7 + 43.4 ngi’g; in five cases with well-differentiated squamous cell cancer, the level of PGBA was 432.2 2 44.8 rig/g..The difference between these levels was statistically significant (P < ,001). It therefore appears that tumor differentiation effects the levels of PGBA (Fig 3). When we compared the level of serum PGBA before surgery in larynx cancer patients (57.6 + 4 ng/mL) with that of the control group (20.5 + 3.2 ng/mL), the difference between them was significant (P < .OOl). The level of PGBA is increased in the serum of patients with larynx cancer. We observed that in 43 patients with larynx cancer, the level of serum PGBA (57.6 + 4 ng/mL) was reduced to 37 f 4 ng/mL on the 10th day
TABLE 2. Supraglottic Cancers According to TNMSystem N,
NI
Total
proximate value of serum PGBA was 20.5 * 3.2 ng/mL. When we compared the approximate level of PGBA (20.5 + 3.2 ng/mL) obtained for the control group with the approximate level of PGBA (57.6 + 4.0 ng/mL) obtained for patients with larynx cancer before the operation, the difference was significant (P < .OOl) (Fig 1). In 43 patients with larynx cancer, the levels of PGBA in tumor specimens ranged from 90 rip/gto 987 rig/g..The approximate level of PGBA was 417.1 k 33.8rig/g..The level of PGBA obtained from samples of normal larynx mucosa was approximately 153.8 + 15.3 rig/g(Fig 2).
SUPRAGLOTTIC STAGE
N,
TABLE 4.
TOTAL
SUBGLOTTIC STAGE
5 8 11 2
Tl
26
Total
T, T, T,
Subglottic Cancers According TNM System N,
N,
-
l-
-
-
N, 2 -
to
N,
TOTAL
-
1 2 -
-
3
a3
CENIKETAL
500
60
100
300
200 -.
E -
I__ ’ -- -
Preop
Control
100
Figure 1. Serum PGBA levels for 20 controls and in patients with larynx carcinoma before and after laryngectomy.
after laryngecomy [Fig 1).The difference between the levels of PGBA preoperatively and postoperatively is statistically significant (P < .OOl). When it became known that PGs accelerated tumor growth and that the levels of PGs were high in human malignant tumors, drugs such as aspirin and indomethacine, shown to be PG synthesis inhibitors in vivo, were considered possible therapeutic agents3”-*’ Some studies show that when PG synthesis inhibitors are used, the growth of tumors can be
500
LOO
--I
3oc Q c” 200 2 : 100
Jmor Figure 2. specimens
”
Normal
PGBA levels in tumor tissue and normal mucosal from patients with larynx carcinoma.
I
.-
-
Fostop
-I
lndlf fcrmtia Figure 3. PGBA levels related to the histologic differentiation of larynx carcinoma.
G&tia according
to
slowed, achieving positive results.36,37 But, to be successful in this regard, we should first know the amount and type of PG present in all human malignant tumors. References 1. Barner HB, Kaiser GC, Jellinek M, et al: Effect of Prostaglandin A on several vascular beds in man. Am Heart J 1973; 85:584-592. 2. Bedwani JR: Biological roles of the prostaglandins. Pharmaceut J 1974; 26:71-74 3. Behrman HR, Rahway NJ, Anderson GG: Prostaglandins in reproduction. Arch Intern Med 1974; 133:77-84 4. Karmali AR: Review: Prostaglandins and cancer prostaglandins. Medicine 1980; 5:11-28 5. Lee H, Sanders RR, Jones WR: Prostaglandin F, and tumors of the female genitalia. Br Med J 1978; 2:434-437 6. Moncada S, Flower RJ, Vane JR: Prostaglandins, Prostacycline and tromboxane A,, in Goodman, Gilman (eds): The Pharmacological Basis of Therapeutics. ed 7. New York, NY, Macmillan, 1985, pp 660-673 7. Wolfe GLG, Coceani F: The role of prostaglandins in the central nervous system. Annu Rev Physiol 1939; 41:669-671 8. Bhana P, Hillier K, I&rim SMM: Vasoactive substances in Kaposis Sarcoma. Cancer 1977; 27:233-235 9. Humes JL, Cupo JJ, Strausse HR: Effects of indomethacine on Maloney Sarcoma virus induced tumors. Prostaglandins 1974; 6:463-473 10. Leaper DJ, French BT, Bennet A: Breast cancer and prostaglandins. A New approach to treatment. Br J Surg 1976; 66:683-686 11. Mortel R, Allegra JC, Demers LM, et al: Plasma prostaglandins across the tumor bed of patients with gynecologic malignancy. Cancer 1977; 39:2201-2203 12. Tan WC, Privett OS, Goldyne ME: Studies of prostaglandins in rat mammary tumors induced by 7,12 dimethyl benzanthracene. Cancer Res 1974; 34:3229-323X 13. Tashjian AH, Voekel LF, Goldhaber et al: Successful treatment of hypercalcemia by indomethacine in mice bearing
84
a prostaglandin 3:515-524 14. Tashjien
LARYNX CANCER AND PROSTAGLANDINS producing
fibrosarcoma.
Prostaglandins
1973;
AH, Voekel EF, MC Donough J, et al: Hydrocortisone inhibits prostaglandin production by mouse fibrosarcoma cell. Nature 1975; 258:739-740 15. Lupulescu A: Effect of prostaglandins on skin tumorgenesis. Experiencia 1978; 34:785-788 16. Lupulescu A: Enhancement of carcinogenesis by prostaglandins in male albino Swiss mice. J Nat1 Cancer Inst 1978; 31:97-106 17. Lupulescu A: Enhancement of carcinogenesis by prostaglandins. Nature 1978; 272634-636 18. Kayaalp 0: Rasyonel tedavi ydniinden tibbi farmakoloji. ~013. Ulucan matbasi, Ankara, Turkey, 1986, pp 25042505 19. Robinson BF, Colier JB, Karim SMM, et al: Effect of prostaglandins A,,A,,B,E,, and F, on forearm arterial bed and superficial hand veins in man. Clin Sci 1973; 44:367-376 20. Bennet A, Haris M, Jenkins MV: The role of prostaglandins in bone resorbtion by dental cysts. Fed POG 1973; 32:804807 21. Bhide MB, Goom RB: Prostaglandins and asthma. Brit Med J 1975; 3:769-772 22. Cole DF, Unger WG: Prostaglandins as mediators for the eye to trauma. Exp Eye Res 1968; 17:357-358 23. Pike JE: The Prostaglandins. J Invest Dermatol 1976; 87:650-653 24. Zurler RB, Qualitata C: Effect of prostaglandin E, on adjuvant arthritis. Nature 1971; 234-237 25. Williams ED, Karim SMM, Sandier W: Prostaglandin secration by medullary carcinoma of the thyroid. Lancet 1968; 1:22-23 26. Bennet A, Del Tacca M: Prostaglandins in human coIonic carcinoma. Gut 1975; 16:409-411 27. Bennet A. Charlier MC. Donald AM, et al: Bone destruction by breast turnours. Prostaglandins 1976; 11:461-464 28. Bennet A, Del Tacca M, Stamford IF, et al: Prostaglandins extracted from tumors of human large bowel. Br J Cancer 1971; 35:811-814 29. McKay HA, Gavrel GJ, Mechan WL, et al: Prostaglandin mediated hypercalcemia in transional cell carcinoma of the bladder. J Urol 1978; 119:689-691
30. Bennet AA, Berstock DA, Raja B, et al: Survival time after surgery increasingly related to the amount of prostaglandins extracted from breast cancers. Br J Pharmacol 1979; 66:451-454 31. Bennet A, Carter RI, Stamford IF, et al: Prostaglandinlike material extracted from squamous carcinomas of the head and neck. Br J Cancer 1980; 41:204-298 32. Jung TTK, Berlinger NT, Juhn SK: Prostaglandins in squamous cell carcinoma of the head and neck: A preliminary study. Laryngoscope 1985; 95:307-360 33. Panje WR: Regression of head and neck carcinoma with prostaglandin synthesis inhibitor. Arch Otolaryngol 1981; 107:658-661 34. Balch CM, Daughterty PA, Tilden AB: Excessive prostaglandin E, production by suppression monocytes in head and neck cancer patients. Ann Surg 1982; 196:645-648 35. Hirch B, Johnson JT, Rabin BS, et al: Immunostimulation of patients with head and neck cancer. Arch Otolaryngol 1983; 109:298-301 36. Bennet A, Hougton J, Leaper DJ, et al: Tumor growth and response to treatment, beneficial effect of the prostaglandin synthesis inhibitor flurbiprofen. Br J Pharmacol 1987; 63:357360 37. Bennet A, Hougton J, Leaper DJ, et al: Cancer growth response to treatment and survival time in mice: Beneficial effect of the prostaglandin synthesis inhibitor flurbiprofen. Prostaglandins 1979; 17:179-191 38. Hial V, Horokova Z, Schaff RE, et al: Alteration of transplantable tumor growth by aspirin and indomethacine. Studies with two transplantable tumors in mice. Eur J Pharmacoll976; 37:387-376 39. Lynch NR, Casetles M, Astoin M, et al: Mechanism of inhibition of tumor growth by aspirin and indomethacin. Br J Cancer 1978; 38:503-506 40. Plescia OJ, Smith AH, Grinwich K: Subversion of immune system by tumor cells and role of prostaglandins. Proc Nat1 Acad Sci USA 1975: 72:1848-1851 41. Santoro MG, Philpott GW, Jalfe BMM: Inhibition of tumor growth in vivo and in vitro by prostaglandin E. Nature 1976; 263:777-780
1990
Larynx Cancer and Prostaglandins Z~YA CENIK, MD, AYSE CENIK, AND YAVUZ UYAR, MD
Prostaglandin levels in serum, tumor specimens, and normal larynx mucosa were measured before and after laryngectomy in 43 patients with larynx cancer. Related findings described elsewhere in the literature are discussed. AM J OTOLARYNGOL 11:81-84. 01990 by W.B. Saunders Company. Key words: larynx cancer, laryngeal mucosa, prostaglandin levels.
MATERIALS AND METHODS
The etiology of larynx cancer, despite its importance among malignant tumors of head and neck origin, has yet to be clarified. The action of some carcinogenic factors is accepted. The most important of these are smoking, alcohol, and chronic irritation. Larynx cancer occurs predominately in males, suggesting the possibility of a normal effect in its causation. Until now, a normal contribution to the etiology of larynx cancer has not been demonstrated. Prostaglandins (PGs) are accepted as local tissue hormones and known to have different physiologic effects. High prostaglandin levels have been measured in malignant tumors of different systems, and their study has caused new concepts to arise concerning cancer etiopathogenesis.l-I4 As tumor growth progressed, it was understood that PGs were synthesized more than normal due to changing tissue biochemistry, so that they were thought to act as a cocarcinogen in the development of malignant tumors.‘5S17 Studies investigating the levels of PGs in the malignant tumors of different systems in human beings have been reported. However, we could find no studies concerning the relationship between larynx cancer and PGs in our review of the literature. Therefore, we undertook, in this study, to measure the levels of PG in sera, tumor tissues and normal larynx mucosa before and after laryngectomy in larynx cancer patients receiving no prior treatment.
Forty-three patients with complaints of hoarseness, air obstruction, and the sensation of obstruction when swallowing were diagnosed as having larynx cancer by laryngoscopic and histopathologic examination, and were entered into our study. Prior to laryngectomy, all patients underwent blood, urea, electrocardiographic, chest x-ray and tests to rule out systemic disorders. All 43 patients were male and all smoked more than 20 cigarettes a day for a long period. The youngest patient was 38 years of age; the oldest was 72. The range of the age is shown in Table 1. Tumor location and stage are shown in Tables 2 through 4. Before laryngectomy, a 4-mL venous blood sample was taken from each patient in a sterile tube with heparm. To determine PG level, the plasma of the samples was separated and kept in closed tubes at -20%. On the 10th day after laryngectomy, 4mL venous blood samples were again taken and processed as before. Twenty subjects without inflammation or tumors comprised the control group. Peripheral venous samples were drawn from the control group, and PG levels evaluated. A bioassay method was used to measure PGs in tissue extractions and plasma samples. Since the mause gastric fundal muscle used in such as; PGE, PGF; the re-
sults obtained were called PG-like activity (PGBA). Student’s t test was applied in the statistical evaluation of the findings. Extraction and bioassay measurements were taken in the Pharmacology and Toxicology Institute of the Medical Faculty of Hacettepe University.
RESULTS The maximum level of serum PGBA obtained in the 43 patients with larynx cancer before laryngectomy was 126 ng/mL; the minimum level was 18 ng/mL, and the approximate serum level was 57. 6 + 4.0 ng/mL. After the operation, a reduction was observed in serum PGBA value. On the 16th postoperative day, the level of serum PGBA was 37.0 ? 4.0 ng/ mL. In the 20 subjects forming our control group, the maximum serum PGBA was 2 ng/mL. The ap-
Received June 1, 1989, from the Departments of Otolaryngology and Pharmacologv, School of Medicine. Ankara and fiacettepe University, Ankara, Turkey. Accepted for publication July 28, 1989. Address reprint requests to Ziya Cenik, MD, Seyh Sadrettin Mahallesi Turgutoglu Sokak, Dural Apartmani no. 1315 Konya, Turkey. 0 1990 by W.B. Saunders Company. 0196-0709/90/1102-0005$5.00/O
81
82
LARYNX CANCER AND PROSTAGLANDINS
TABLE 3. Glottic Cancers According to TNM System
TABLE 1. Age Distribution of the Patients
GLOTTIC STAGE
NO.OF~ATIENTS
AGE O-10
11-20 21-30 31-40 41-50 51-60 61-70 71-80
2 9 21 10 1
Total
43
Tl T, T, T,
DISCUSSION It has been proven that PGs are present in all tissues.” They exert a regulatory effect on various systems such as the urinary, cardiovascular, and especially the reproductive system.*-3,5-7,15*18,1g It is understood that PGs have effects other than those related to tumor growth.20*24Their effects on the proliferation of malignant cells and on tumor progress have been the most important areas of study. Prostaglandins were first detected in human malignant tumors in thyroid cancer by Williams et al in 1968.25 Bennet and colleagues26-28 reported that PG levels in tumor tissue were higher than in normal tissues and that PGs played a role in tumor progression. The levels of PGs in human tumor have been investigated by a number of investigators.
TI T, T, T*
Total
2 -
N, 3 5 4 -
N, 3 5 1
N,
N,
TOTAL
2 1
1 2 1 -
3 3 -
1
3 6 4 -
-
N, 2 1
14
Most of these studies concern thyroid, breast, and genital cancers.5**1*2g*30 Recently, increased levels of PG, especially of PGE,, have been reported in the tumor tissues of patients with head and neck carcinoma.31p32 Panje, 33 Balch et a1,34 Hirch et a1.35 suggested that PGE, may play a role in the inhibition of cellmediated immunity in head and neck cancer patients. In the 43 larynx cancer patients we examined, the level of PGBA was approximately 417.1 + 33.8rig/g..The average level of PGBA in the same patients was 153.8 rig/gin normal larynx mucosa samples. The difference between these levels is statistically significant (P < .OOl), and it shows that the level of PGs is high in larynx cancers, as it is in other malignant tumors (Fig 2). In our study, we tried to determine whether a relationship exists between the levels of PGBA and the histologic differentiation of the tumor. In three patients with undifferentiated squamous cell cancer, the level of PGBA was 240.7 + 43.4 ngi’g; in five cases with well-differentiated squamous cell cancer, the level of PGBA was 432.2 2 44.8 rig/g..The difference between these levels was statistically significant (P < ,001). It therefore appears that tumor differentiation effects the levels of PGBA (Fig 3). When we compared the level of serum PGBA before surgery in larynx cancer patients (57.6 + 4 ng/mL) with that of the control group (20.5 + 3.2 ng/mL), the difference between them was significant (P < .OOl). The level of PGBA is increased in the serum of patients with larynx cancer. We observed that in 43 patients with larynx cancer, the level of serum PGBA (57.6 + 4 ng/mL) was reduced to 37 f 4 ng/mL on the 10th day
TABLE 2. Supraglottic Cancers According to TNMSystem N,
NI
Total
proximate value of serum PGBA was 20.5 * 3.2 ng/mL. When we compared the approximate level of PGBA (20.5 + 3.2 ng/mL) obtained for the control group with the approximate level of PGBA (57.6 + 4.0 ng/mL) obtained for patients with larynx cancer before the operation, the difference was significant (P < .OOl) (Fig 1). In 43 patients with larynx cancer, the levels of PGBA in tumor specimens ranged from 90 rip/gto 987 rig/g..The approximate level of PGBA was 417.1 k 33.8rig/g..The level of PGBA obtained from samples of normal larynx mucosa was approximately 153.8 + 15.3 rig/g(Fig 2).
SUPRAGLOTTIC STAGE
N,
TABLE 4.
TOTAL
SUBGLOTTIC STAGE
5 8 11 2
Tl
26
Total
T, T, T,
Subglottic Cancers According TNM System N,
N,
-
l-
-
-
N, 2 -
to
N,
TOTAL
-
1 2 -
-
3
a3
CENIKETAL
500
60
100
300
200 -.
E -
I__ ’ -- -
Preop
Control
100
Figure 1. Serum PGBA levels for 20 controls and in patients with larynx carcinoma before and after laryngectomy.
after laryngecomy [Fig 1).The difference between the levels of PGBA preoperatively and postoperatively is statistically significant (P < .OOl). When it became known that PGs accelerated tumor growth and that the levels of PGs were high in human malignant tumors, drugs such as aspirin and indomethacine, shown to be PG synthesis inhibitors in vivo, were considered possible therapeutic agents3”-*’ Some studies show that when PG synthesis inhibitors are used, the growth of tumors can be
500
LOO
--I
3oc Q c” 200 2 : 100
Jmor Figure 2. specimens
”
Normal
PGBA levels in tumor tissue and normal mucosal from patients with larynx carcinoma.
I
.-
-
Fostop
-I
lndlf fcrmtia Figure 3. PGBA levels related to the histologic differentiation of larynx carcinoma.
G&tia according
to
slowed, achieving positive results.36,37 But, to be successful in this regard, we should first know the amount and type of PG present in all human malignant tumors. References 1. Barner HB, Kaiser GC, Jellinek M, et al: Effect of Prostaglandin A on several vascular beds in man. Am Heart J 1973; 85:584-592. 2. Bedwani JR: Biological roles of the prostaglandins. Pharmaceut J 1974; 26:71-74 3. Behrman HR, Rahway NJ, Anderson GG: Prostaglandins in reproduction. Arch Intern Med 1974; 133:77-84 4. Karmali AR: Review: Prostaglandins and cancer prostaglandins. Medicine 1980; 5:11-28 5. Lee H, Sanders RR, Jones WR: Prostaglandin F, and tumors of the female genitalia. Br Med J 1978; 2:434-437 6. Moncada S, Flower RJ, Vane JR: Prostaglandins, Prostacycline and tromboxane A,, in Goodman, Gilman (eds): The Pharmacological Basis of Therapeutics. ed 7. New York, NY, Macmillan, 1985, pp 660-673 7. Wolfe GLG, Coceani F: The role of prostaglandins in the central nervous system. Annu Rev Physiol 1939; 41:669-671 8. Bhana P, Hillier K, I&rim SMM: Vasoactive substances in Kaposis Sarcoma. Cancer 1977; 27:233-235 9. Humes JL, Cupo JJ, Strausse HR: Effects of indomethacine on Maloney Sarcoma virus induced tumors. Prostaglandins 1974; 6:463-473 10. Leaper DJ, French BT, Bennet A: Breast cancer and prostaglandins. A New approach to treatment. Br J Surg 1976; 66:683-686 11. Mortel R, Allegra JC, Demers LM, et al: Plasma prostaglandins across the tumor bed of patients with gynecologic malignancy. Cancer 1977; 39:2201-2203 12. Tan WC, Privett OS, Goldyne ME: Studies of prostaglandins in rat mammary tumors induced by 7,12 dimethyl benzanthracene. Cancer Res 1974; 34:3229-323X 13. Tashjian AH, Voekel LF, Goldhaber et al: Successful treatment of hypercalcemia by indomethacine in mice bearing
84
a prostaglandin 3:515-524 14. Tashjien
LARYNX CANCER AND PROSTAGLANDINS producing
fibrosarcoma.
Prostaglandins
1973;
AH, Voekel EF, MC Donough J, et al: Hydrocortisone inhibits prostaglandin production by mouse fibrosarcoma cell. Nature 1975; 258:739-740 15. Lupulescu A: Effect of prostaglandins on skin tumorgenesis. Experiencia 1978; 34:785-788 16. Lupulescu A: Enhancement of carcinogenesis by prostaglandins in male albino Swiss mice. J Nat1 Cancer Inst 1978; 31:97-106 17. Lupulescu A: Enhancement of carcinogenesis by prostaglandins. Nature 1978; 272634-636 18. Kayaalp 0: Rasyonel tedavi ydniinden tibbi farmakoloji. ~013. Ulucan matbasi, Ankara, Turkey, 1986, pp 25042505 19. Robinson BF, Colier JB, Karim SMM, et al: Effect of prostaglandins A,,A,,B,E,, and F, on forearm arterial bed and superficial hand veins in man. Clin Sci 1973; 44:367-376 20. Bennet A, Haris M, Jenkins MV: The role of prostaglandins in bone resorbtion by dental cysts. Fed POG 1973; 32:804807 21. Bhide MB, Goom RB: Prostaglandins and asthma. Brit Med J 1975; 3:769-772 22. Cole DF, Unger WG: Prostaglandins as mediators for the eye to trauma. Exp Eye Res 1968; 17:357-358 23. Pike JE: The Prostaglandins. J Invest Dermatol 1976; 87:650-653 24. Zurler RB, Qualitata C: Effect of prostaglandin E, on adjuvant arthritis. Nature 1971; 234-237 25. Williams ED, Karim SMM, Sandier W: Prostaglandin secration by medullary carcinoma of the thyroid. Lancet 1968; 1:22-23 26. Bennet A, Del Tacca M: Prostaglandins in human coIonic carcinoma. Gut 1975; 16:409-411 27. Bennet A. Charlier MC. Donald AM, et al: Bone destruction by breast turnours. Prostaglandins 1976; 11:461-464 28. Bennet A, Del Tacca M, Stamford IF, et al: Prostaglandins extracted from tumors of human large bowel. Br J Cancer 1971; 35:811-814 29. McKay HA, Gavrel GJ, Mechan WL, et al: Prostaglandin mediated hypercalcemia in transional cell carcinoma of the bladder. J Urol 1978; 119:689-691
30. Bennet AA, Berstock DA, Raja B, et al: Survival time after surgery increasingly related to the amount of prostaglandins extracted from breast cancers. Br J Pharmacol 1979; 66:451-454 31. Bennet A, Carter RI, Stamford IF, et al: Prostaglandinlike material extracted from squamous carcinomas of the head and neck. Br J Cancer 1980; 41:204-298 32. Jung TTK, Berlinger NT, Juhn SK: Prostaglandins in squamous cell carcinoma of the head and neck: A preliminary study. Laryngoscope 1985; 95:307-360 33. Panje WR: Regression of head and neck carcinoma with prostaglandin synthesis inhibitor. Arch Otolaryngol 1981; 107:658-661 34. Balch CM, Daughterty PA, Tilden AB: Excessive prostaglandin E, production by suppression monocytes in head and neck cancer patients. Ann Surg 1982; 196:645-648 35. Hirch B, Johnson JT, Rabin BS, et al: Immunostimulation of patients with head and neck cancer. Arch Otolaryngol 1983; 109:298-301 36. Bennet A, Hougton J, Leaper DJ, et al: Tumor growth and response to treatment, beneficial effect of the prostaglandin synthesis inhibitor flurbiprofen. Br J Pharmacol 1987; 63:357360 37. Bennet A, Hougton J, Leaper DJ, et al: Cancer growth response to treatment and survival time in mice: Beneficial effect of the prostaglandin synthesis inhibitor flurbiprofen. Prostaglandins 1979; 17:179-191 38. Hial V, Horokova Z, Schaff RE, et al: Alteration of transplantable tumor growth by aspirin and indomethacine. Studies with two transplantable tumors in mice. Eur J Pharmacoll976; 37:387-376 39. Lynch NR, Casetles M, Astoin M, et al: Mechanism of inhibition of tumor growth by aspirin and indomethacin. Br J Cancer 1978; 38:503-506 40. Plescia OJ, Smith AH, Grinwich K: Subversion of immune system by tumor cells and role of prostaglandins. Proc Nat1 Acad Sci USA 1975: 72:1848-1851 41. Santoro MG, Philpott GW, Jalfe BMM: Inhibition of tumor growth in vivo and in vitro by prostaglandin E. Nature 1976; 263:777-780