Discrepancy between in vitro and in vivo antitumor effect of a new platinum(II) metallointercalator.
Platinum(II) metallointercalators represent a new class of DNA-damaging antitumor complexes active in cisplatin- and oxaliplatin-resistant cell lines. In the first part of our work, we have screened in vitro a serie of 18 metallointercalators with the structure [Pt(A(L))(I(L))](2+) where A(L) = ethylenediamine (EN) or diaminocyclohexane in R,R- (RR) or S,S- (SS) configuration ; and I(L) = 1,10-phenanthroline with different degree of methylation : no methylation (PHEN), mono-methylated in position 4 (4ME) or 5 (5ME), or di-methylated in positions 4 and 7 (47ME) or in positions 5 and 6 (56ME) or tetramethylated in positions 3,4,7 and 8 (3478ME). Eight compounds: PHENEN, 56MEEN, 47MERR, 56MERR, 4MESS, 5MESS, 47MESS and 56MESS exhibited significant cytotoxic effect, equivalent or higher than cisplatin, oxaliplatin or carboplatin in the human HCT8 colon and IGROV1 ovarian cancer cell lines for both 1 and 24 h incubation time. The high cytotoxicity of the most active compound, the 56MESS, could be related to the hydrophobicity of the phenanthroline ligand that increases cellular uptake in human HCT8, HT29 (colon) and IGROV1 (ovarian) as well as in rat PROb colon cell lines. Unfortunately, intravenous or intraperitoneal administration of 56MESS had no antitumoral activity in BD-IX rats with peritoneal carcinomatosis induced by an intraperitoneal PROb cells inoculation. Moreover, 56MESS displayed nephrotoxicity at pharmacological dose. Thus, these data query the in vivo/in vitro correlation and reconsider the place of the in vivo screening to select adequate candidate drug for further preclinical and clinical developments.
Faculties of Medicine and Pharmacy, INSERM, UMR 866, University of Burgundy, 7 Bd Jeanne d'Arc, BP 87900, 21079, Dijon Cedex, France.
Johnny
J
Moretto
Bruno
B
Chauffert
François
F
Ghiringhelli
Janice R
JR
Aldrich-Wright
Florence
F
Bouyer
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000473:pathology; D017671:Platinum Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors
D000970:Antineoplastic Agents; D007364:Intercalating Agents; D017671:Platinum Compounds