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Comparison of the pharmacological profile of an olivacine derivative and a potential prodrug.
Cancer Chemother Pharmacol. 2002 Aug; 50(2):95-103.CC

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.

PURPOSE

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+Show Affiliations

Institut de Recherches Servier, Division de Cancérologie, 11 rue des Moulineaux, 92150 Suresnes, France. laurence.kraus-berthier@fr.netgrs.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

12172972

Citation

Kraus-Berthier, Laurence, et al. "Comparison of the Pharmacological Profile of an Olivacine Derivative and a Potential Prodrug." Cancer Chemotherapy and Pharmacology, vol. 50, no. 2, 2002, pp. 95-103.
Kraus-Berthier L, Guilbaud N, Léonce S, et al. Comparison of the pharmacological profile of an olivacine derivative and a potential prodrug. Cancer Chemother Pharmacol. 2002;50(2):95-103.
Kraus-Berthier, L., Guilbaud, N., Léonce, S., Parker, T., Genissel, P., Guillonneau, C., Goldstein, S., Atassi, G., & Pierré, A. (2002). Comparison of the pharmacological profile of an olivacine derivative and a potential prodrug. Cancer Chemotherapy and Pharmacology, 50(2), 95-103.
Kraus-Berthier L, et al. Comparison of the Pharmacological Profile of an Olivacine Derivative and a Potential Prodrug. Cancer Chemother Pharmacol. 2002;50(2):95-103. PubMed PMID: 12172972.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparison of the pharmacological profile of an olivacine derivative and a potential prodrug. AU - Kraus-Berthier,Laurence, AU - Guilbaud,Nicolas, AU - Léonce,Stéphane, AU - Parker,Tracy, AU - Genissel,Patrick, AU - Guillonneau,Claude, AU - Goldstein,Solo, AU - Atassi,Ghanem, AU - Pierré,Alain, Y1 - 2002/06/25/ PY - 2002/01/10/received PY - 2002/05/17/accepted PY - 2002/8/13/pubmed PY - 2002/10/9/medline PY - 2002/8/13/entrez SP - 95 EP - 103 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother. Pharmacol. VL - 50 IS - 2 N2 - 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. PURPOSE: 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. SN - 0344-5704 UR - https://www.unboundmedicine.com/medline/citation/12172972/Comparison_of_the_pharmacological_profile_of_an_olivacine_derivative_and_a_potential_prodrug_ L2 - https://dx.doi.org/10.1007/s00280-002-0481-z DB - PRIME DP - Unbound Medicine ER -