Ether lipid derivatives: antineoplastic activity in vitro and the structure-activity relationship.
The antineoplastic activity of two ether lipid derivatives, the alkyl-lysophospholipid derivative (ALP) ET-18-OCH3 and the ether-linked lipoidal amine CP-46,665 was tested in a human tumor clonogenic assay (HTCA) in vitro. CP-46,665 suppressed the colony formation of various human tumors with a slight dose response relation after 1 hr incubation and with a clear optimum (85% response rate) after continuous exposure in the higher dose range tested (10 micrograms/ml). ET-18-OCH3 did not have substantial activity after 1 hr of incubation. However, when continuous exposure to the compound was used, ET-18-OCH3 seemed to have a modest dose response effect and yielded a response in about 60% of the tumor cell samples tested in the higher dose range (10 micrograms/ml). Thus, both compounds have in vitro antitumor activity in the HTCA within a dose range of 1-10 micrograms/ml, especially during continuous exposure. The tumor specific type activity was found in breast cancer, ovarian cancer, lung cancer and mesothelioma. Both compounds caused decreases in colony formation down to the 0%, 2% and 4% levels. In a comparison of specimens in which both compounds were used, only one of five times showed a discordance in sensitivity or resistance; therefore the compounds appear similar in their in vitro activity. In a second set of experiments we tested the structure-activity relationship among a variety of ALP in the [3H]thymidine incorporation assay after incubation with HL-60 leukemic blasts and other neoplastic cells from human origin.(ABSTRACT TRUNCATED AT 250 WORDS)
W E
WE
Berdel
D D
DD
Von Hoff
C
C
Unger
H D
HD
Schick
U
U
Fink
A
A
Reichert
H
H
Eibl
J
J
Rastetter
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D008244:Lysophosphatidylcholines / Q000627:therapeutic use* / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010742:Phospholipid Ethers; D010880:Piperidines / Q000627:therapeutic use* / Q000633:toxicity; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D008244:Lysophosphatidylcholines; D010742:Phospholipid Ethers; D010880:Piperidines; C026659:edelfosine; C038408:CP 46665