ANTITUMOR-ACTIVITY OF DELTA-7-PROSTAGLANDIN A1 AND DELTA-12-PROSTAGLANDIN J2 INVITRO AND INVIVO

  • 1 July 1986
    • journal article
    • research article
    • Vol. 46  (7) , 3538-3542
Abstract
Cyclopentenone prostaglandins (PGs) such as prostaglandin A1 (PGA1) and prostaglandin J2 (PGJ2) significantly increased the life span of Ehrlich ascites tumor-bearing mice. In order to obtain PG derivatives which have more potent antitumor activity than PGA1 and PGJ2, we synthesized a number of alkylidenecyclopentenone PGs and studied the antitumor activity of these compounds in vitro and in vivo. .DELTA.7-PGA1, 12-epi-.DELTA.7-PGA1, and .DELTA.12,14-PGJ showed 50% inhibitory concentrations of 0.3 .mu.g/ml against the growth of L1210 culture cells. These compounds are several times more cytotoxic than parent compounds. From a structure-activity relationship analysis, we concluded that, as for PGA derivatives: (a) a double bond in C7-8 potentiates the cytotoxicity (b) a 15-hydroxy group is not essential for cytotoxicity; (c) the stereochemistry of R2 chain is not essential, while 12-epi derivatives also have full activity; (d) a double bond in C12-13 seems to be essential for full activity, and for PGJ derivatives a double bond in C12-13 and C14-15 potentiates the cytotoxicity. These compounds showed marked antitumor activity against Ehrlich ascites tumor in vivo. At doses of 20-30 mg/kg/day three or five consecutive i.p. treatments with these compounds resulted in a 66 to 111% increase in life span with long-term survivors. A single i.p. injection with 12-epi-.DELTA.7-PGA1 (100 mg/kg) resulted in 73% increase in life span with 33% of long-term survivors, indicating an activity comparable to that of cyclophosphamide (200 mg/kg). However, .DELTA.7-PGA1, and 12-epi-.DELTA.7-PGA1 were marginally effective against P388 leukemia. Treatment with .DELTA.7-PGA1 (10 mg/kg/day i.p.) and 12-epi-.DELTA.7-PGA1 (20 mg/kg/day i.p.) on Days 1-9 resulted in 25.8 and 29.6% increases in life span, respectively. .DELTA.7-PGA1 and .DELTA.12-PGJ2 derivatives may be a potential new class of antitumor agents.

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