Antitumor activity of delta 7-prostaglandin A1 and delta 12-prostaglandin J2 in vitro and in vivo.
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-PGJ2 showed 50% inhibitory concentrations of 0.3 microgram/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.
Kato
T
T
Fukushima
M
M
Kurozumi
S
S
Noyori
R
R
D000818:Animals; D000970:Antineoplastic Agents; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D015230:Prostaglandin D2 / Q000031:analogs & derivatives*; D011454:Prostaglandins A / Q000627:therapeutic use*; D011457:Prostaglandins D / Q000627:therapeutic use*; D011465:Prostaglandins, Synthetic / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011454:Prostaglandins A; D011457:Prostaglandins D; D011465:Prostaglandins, Synthetic; C037112:9-deoxy-delta-9-prostaglandin D2; D015230:Prostaglandin D2; C100573:prostaglandin A1