title: Comparison of the pharmacological profile of an olivacine derivative and a potential prodrug.
abstract: BACKGROUND
  The new olivacine derivative S 16020-2 (NSC-659687) has entered clinical trials on the basis of a marked antitumor activity in experimental models. Amongst the analogues which were synthesized to improve both therapeutic index and antitumor activity, the most active ones were those esterified on the 9-OH group such as S 30972-1, the glutaric acid monoester derivative.
  
  
  OBJECTIVE
  To compare the pharmacological profile of S 30972-1 and S 16020-2 in vitro and in vivo and to investigate whether S 30972-1 could act as a prodrug of S 16020-2.
  
  
  METHODS
  The two compounds were compared in vitro in terms of their activity in inhibiting cellular proliferation and perturbing the cell cycle and in vivo in terms of their antitumor activity in murine transplantable tumors and human orthotopic models. The plasma concentrations of S 16020-2 and S 30972-1 were determined in mice, in a comparative pharmacokinetic study after i.v. administration, using an HPLC assay.
  
  
  RESULTS
  Although tumor cell proliferation and accumulation of cells in the G2 phase of the cell cycle were similarly affected by the two compounds after a continuous exposure (IC50 values of 30-50 n M), S 30972-1 was about tenfold less potent than S 16020-2 after short exposures. In vivo, S 30972-1 induced more long-term survivors than S 16020-2 among mice with Lewis lung carcinoma and sensitive or multidrug resistant P388 leukemias. The growth of Colon 38 carcinoma was slightly more inhibited by S 30972-1 than S 16020-2. In the more relevant human orthotopic models, using the optimal doses of each drug, 160 mg/kg S 30972-1 was significantly more active than 80 mg/kg S 16020-2 in the NCI-H460 lung carcinoma. The two compounds were significantly active in A549 lung carcinoma, moderately active in the NIH:OVCAR-3 ovary carcinoma and inactive in the NCI-H125 lung and DU145 prostate carcinomas. Pharmacokinetic study demonstrated that S 30972-1 is a prodrug of S 16020-2: the conversion was rapid and complete within 1 h of the administration of S 30972-1.
  
  
  CONCLUSIONS
  The in vivo profile of these two compounds appeared very similar, although S 30972-1 exhibited globally a wider therapeutic index. The rapid conversion of S 30972-1 to S 16020-2 shows that S 30972-1 acts mainly as a prodrug of S 16020-2. This should be taken into account before considering S 30972-1 as a valuable back-up of S 16020-2.
authors.affiliation: Institut de Recherches Servier, Division de Cancérologie, 11 rue des Moulineaux, 92150 Suresnes, France. laurence.kraus-berthier@fr.netgrs.com
authors.forename: Laurence
authors.initials: L
authors.lastname: Kraus-Berthier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guilbaud
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: Tracy
authors.initials: T
authors.lastname: Parker
authors.forename: Patrick
authors.initials: P
authors.lastname: Genissel
authors.forename: Claude
authors.initials: C
authors.lastname: Guillonneau
authors.forename: Solo
authors.initials: S
authors.lastname: Goldstein
authors.forename: Ghanem
authors.initials: G
authors.lastname: Atassi
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D020296:Animals, Congenic; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000201:enzymology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004611:Ellipticines / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009928:Organ Specificity; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D059005:Topoisomerase II Inhibitors; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays
chemical_list: D004611:Ellipticines; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011355:Prodrugs; C101591:S 16020-2; C418862:S30972-1; D059005:Topoisomerase II Inhibitors; D014747:Vinblastine; D000077235:Vinorelbine