Cytotoxic activity of synthetic aza alkyl lysophospholipids against drug sensitive and drug resistant human tumor cell lines.
The anti-tumor cytotoxic activity of four newly synthesized aza alkyl lysophospholipids (AALP), namely BN 52205, BN 52207, BN 52208 and BN 52211, was investigated. Using the 51Cr release assay, the four compounds were endowed with cytotoxic activity, in a concentration-dependent fashion, against various human tumor cell lines of different histological origin. Two different mechanisms appear to be involved in the AALP-mediated cytotoxicity. A rapid membrane damaging effect was observed in less than one hour's incubation of tumor cells with AALP and cytotoxicity was temperature-independent when AALP were used at greater than or equal to 200 micrograms/ml. A slower cytotoxic mechanism was observed after 18 hours incubation at 37 degrees C when AALP were used at concentrations of 30-100 micrograms/ml. The pattern and magnitube of the cytotoxic activity achieved with all the 4 AALP compounds tested were similar and the cytotoxicity mediated by combination of two compounds was additive. In addition to the cytotoxic effect, the AALP compounds also exerted a cytostatic anti-tumor effect, as assessed by inhibition of 3H TdR incorporation. Using a variety of human tumor cell lines as targets, the cytotoxic effect observed with the AALP was noted with tumor cells that were either sensitive or resistant to TNF-alpha and/or chemotherapeutic drugs such as mitomycin C, adriamycin and cis-platinum. The LD50 toxicity in mice was 100-125 mg/kg. The present findings demonstrate that AALP are cytotoxic to a variety of human tumor cell lines and do not appear to discriminate between drug/cytokine sensitive or resistant cells. Thus the present study suggests that some aza alkyl lysophospholipids may be considered as potential anticancer agents.
Morimoto
H
H
Department of Microbiology and Immunology, UCLA School of Medicine.
Broquet
C
C
Principe
P
P
Mencia-Huerta
J M
JM
Braquet
P
P
Bonavida
B
B
D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D008246:Lysophospholipids / Q000737:chemistry / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D008246:Lysophospholipids; C072522:BN 52205; C072525:BN 52211; C072524:BN 52208; C072523:BN 52207