Antineoplastic activity, synergism, and antagonism of triarylalkylphosphonium salts and their combinations.
Previously, some of us demonstrated that monocationic phosphonium salt [4-(formylphenyl)methyl]triphenylphosphonium chloride (A) and [4-(hydrazinocarboxy)-1-butyl]tris(4-dimethylaminophenyl)phosph oni um chloride (B) in combination, exhibit inhibitory synergism against ELA mammary carcinoma. Here we show that A + B also exhibits synergism against cultured MB49 murine bladder carcinoma, but antagonism against HT-29 human colon carcinoma. This is probably due to assembly of the hydrazone (C) in situ: synthetic C is a more potent growth inhibitor than either A or B for MB49 and ELA, yet inferior to B for HT-29 cells. A, B, C, [4-(hydrazinocarboxy)-1-butyl]tris(3-tolyl)phosphonium chloride (D) and [4-(methylcarboxy)butyl]triphenylphosphonium chloride (F) selectively inhibit carcinoma growth relative to untransformed cells, most likely due to high carcinoma transmembrane potentials. D and F are tolerated in mice at 100 mg/kg. Intraperitoneal administration of D slows subcutaneous HT-29 xenograft growth by 41 to 59% versus controls in nu/nu mice, and intraperitoneal administration of B slows MB49 xenograft growth by 46 to 57% versus controls and extends the median lifespan of mice bearing ELA breast carcinoma allografts by 86%. Triarylalkylphosphonium salts represent a promising class of antineoplastic cations exhibiting unusual selectivity and synergism.
Patel
J
J
Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037.
Rideout
D
D
McCarthy
M R
MR
Calogeropoulou
T
T
Wadwa
K S
KS
Oseroff
A R
AR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats
D009943:Organophosphorus Compounds