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.
AuthorsJ Patel, D Rideout, M R McCarthy, T Calogeropoulou, K S Wadwa, A R Oseroff
JournalAnticancer research (Anticancer Res) 1994 Jan-Feb Vol. 14 Issue 1A Pg. 21-8 ISSN: 0250-7005 [Print] GREECE
PMID8166451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Organophosphorus Compounds
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (antagonists & inhibitors, pharmacology)
  • Cell Division (drug effects)
  • Cercopithecus aethiops
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Organophosphorus Compounds (antagonists & inhibitors, pharmacology)
  • Rats

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