Prostaglandins in the treatment of cancer


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Abstract

Prostaglandins (PGs) with antiproliferative activity against tumor cells consist of the cyclopentenone PGs and the alkylidene cyclopentenone PGs. Such PGs are PGD2, PGJ2, δ12-PGJ2, PGAL δ7-PGA1 and PGA2. Both PGJ2 and δ12-PGJ2 are ultimate metabolites of PGD2 and have potent antiproliferative activity on tumor cells. δ12-PGJ2 was identified in human urine, whereas δ7-PGA1 has not been found In the human body. One Important characteristic of both δ7-PGA1 and δ12-PGJ2 Is that they have little cross resistance with clsplatin and adriamycin In vitro and In vivo, δ7-PGA, has 5-fold greater antitumor activity than δ12-PGJ2. Methyl ester-δ7PGA1 (methyl-δ7-PGA1) Is stable chemically and can be easily synthesized In large amounts. All four Isomers of methyl-δ7-PGA1 showed the same antiproliferative activities on ovarian carcinoma cells. In addition, methyl-δ7-PGA1 integrated in lipid microspheres (llpo-methyl-δ7-PGA1) Is more soluble In water than methyl-δ7-PGA1 alone. Hence, lipo-methyl-δ7-PGA1 was selected for extensive preclinical studies. Intravenous administration of lipo-methyl-δ7-PGA1 could Inhibit the growth of both HeLa S3 and Lovo colon cancer cells transplanted subcutaneously In nude mice. Lipo-methyl-δ7-PGA1 by intraperitoneal administration could prolong the survival of scid mice bearing 2008C/13* cells resistant to cisplatin. The combined administration of cisplatin and lipo-methyl-δ7-PGA1 prolonged the survival of nude mice bearing HRA cells compared with each single agent alone. Consequently, phase 1 clinical studies of lipo-methyl-δ7-PGA1 In refractory ovarian cancer and colon cancer are planned. δ7-PGA1 demonstrates irreversible binding to thiois, whereas PGA1 shows reversible binding. Both δ7-PGA1 and lipo-methyl-δ7-PGA1 are metabolized to unknown products in human serum, whereas the latter is converted to δ7-PGA1 in rat serum. The half-life of δ7-PGA1 was 1.5 h in human serum, whereas that of methyl-δ7-PGA1 was 13 min. The half-life of lipo-methyl-δ7-PGA1 was almost the same as that of methyl-δ7-PGA1. On the other hand, δ12-PGJ2 was stable in human serum. Lipo-methyl-δ7-PGA1 showed less toxicity than δ7-PGA1 and δ12-PGJ2. LD10 and LD50 for single administration were 17.4 and 33.5 mg/kg for male rats, and 38.1 and 45.9 mg/kg for female rats, respectively. All rats tolerated repeated administration of 10 mg/kg/day lipo-methyl-δ7-PGA1 for 28 days. However, loss of weight was observed after 14 days of administration. Slight anemia was recognized with decrease of both red blood cell count and hemoglobin. However, the dose-limiting factors remain undetermined. The inhibition of DNA synthesis by antitumor PGs Is Independent of AMP. PGs were transferred into the nucleus, and δ12-PGJ2 covalently bound to nuclear proteins and inhibited RNA synthesis. With respect to their antiproliferative activity, the primary effect of PGA1, PGD2, δ7-PGA1 and δ12-PGJ2 was to block cell progression from G1 to S in the cell cycle. Both PGA1 and PGJ2 Induced the synthesis of a 70 kDa protein (p70) which was Identified as a heat shock protein related to the major 70 kDa heat shock protein group. The G1 block is associated with both inhibition of myc gene family expression and Induction of heat shock proteins. High dose administration of either PGA2 or δ12-PGJ2 resulted in significant G2/M arrest and apoptosis. The PGs with a cyclopentenone ring have antiviral activity. PGJ2 is a potent antiviral agent against Sendal virus and herpes simplex virus. In addition, PGA1 and 16,16-di-methyl-PGA2-methylester suppressed the proliferation of HIV-1-Infected cord blood lymphocytes In vitro. The potency of antiviral activity was δ7-PGA1 > PGA1 > PGA2. The cyclopentenone ring seems to have a universal action of both antitumor activity and antiviral DNA activity.

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