Activity of two platinum-linked phosphonic acids against autochthonous rat colorectal cancer as well as in two human colon-cancer cell lines.
Two new platinum-containing phosphonate compounds, cis-diammine[nitrilotris(methylphosphonato)(2-)- O1,N1]platinum(II) (AMDP) and cis-cyclohexane-1,2-diamine[nitrilotris(methylphosphonato) (2-)-O1,N1]platinum(II) (DADP) were investigated in acetoxy-methyl-methylnitrosamine-induced autochthonous colorectal rat adenocarcinoma in vivo as well as in two human colon-cancer cell lines (SW707 and SW948) in vitro. In the in vivo model, the two compounds were given i.v. at doses of 8 and 13 mg/kg as well as p.o. at 16 and 26 mg/kg twice a week for 10 weeks, respectively. AMDP produced more intensive toxicity at both doses but showed higher antitumour activity only following i.v. administration. On the other hand, DADP caused significant tumour-growth inhibition after both modes of application, but as it produced only low toxicity, its use should be favoured. The in vitro assays were performed using two cell lines derived from human colorectal adenocarcinomas. According to the microculture tetrazolium test (MTT) AMDP (IC50, 34 and 59 microM in SW707 and SW948, respectively) was more effective than DADP (IC50, 412 and 660 microM in SW707 and SW948, respectively) in inhibiting cell growth. Based on cell counts AMDP (IC50, 8 and 11 microM in SW707 and SW948, respectively) and DADP (IC50, 266 and 285 microM in SW707 and SW948, respectively) showed more intensive antiproliferative efficacy as determined by the Coulter Counter method vs the MTT assay. The promising activities of these new platinum-linked phosphonic acids in autochthonous rat colorectal carcinoma and in human colorectal cancer cell lines warrant further investigations of compounds of this class to elucidate their role in the treatment of colorectal cancer.
Galeano
A
A
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg.
Berger
M R
MR
Keppler
B K
BK
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D063065:Organophosphonates / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013778:Tetrazolium Salts; D013844:Thiazoles; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D009944:Organoplatinum Compounds; D013778:Tetrazolium Salts; D013844:Thiazoles; C064516:aminotris(methylenephosphonato)diamminoplatinum (II); C068853:diamminecyclohexanoaminotrismethylenephosphonatoplatinum(II); C022616:thiazolyl blue