Cellular bases of the antitumor activity of a 7-substituted camptothecin in hormone-refractory human prostate carcinoma models

Valentina Zuco, Rosanna Supino, Michelandrea De Cesare, Nives Carenini, Paola Perego, Laura Gatti, Graziella Pratesi, Claudio Pisano, Roberta Martinelli, Federica Bucci, Romina Zanier, Paolo Carminati, Franco Zunino

Research output: Contribution to journalArticle

Abstract

ST1481, a lead compound of a novel potent 7-substituted lipophilic camptothecin series, is able to overcome several mechanisms of drug resistance and was selected for clinical development. This study was designed to examine the antitumor activity of ST1481 in the treatment of preclinical models of human p53-defective hormone-refractory prostate carcinoma (DU145, PC3, and JCA-1) and to explore the cellular bases of the efficacy of camptothecins. A cellular pharmacology study (cytotoxicity, apoptosis, cellular drug accumulation, DNA damage, and cell cycle perturbation) was performed in DU145 and PC3 cells, characterized by a different cell cycle checkpoint status. The introduction of wild-type p53 in PC3 cells appreciably decreased the drug sensitivity. The 7-substituted camptothecins exhibited a high cytotoxic potency that paralleled their relative ability to induce DNA damage and a substantially increased cellular accumulation as compared to topotecan. The cytotoxic effect of camptothecins in DU145 cells was associated with arrest in S phase and early activation of apoptosis, whereas PC3 cells responded to drugs by a persistent block in G2 phase with a cytostatic effect and a late apoptosis. The efficiency of S phase checkpoint in DU145 cells was supported by a time-dependent decrease of DNA synthesis following treatment. In spite of an apparent cytostatic response and apoptosis resistance, the PC3 tumor was more responsive to in vivo treatment with camptothecins than the DU145 model. Indeed, the therapeutic outcome did not reflect the cell susceptibility to early activation of apoptosis. We suggest that cell death in PC3 cells is a delayed event consequent to persistent arrest in G2 and insufficient repair of DNA damage. ST1481 was appreciably more effective than topotecan in all tested tumors. In conclusion, the results indicated a relevant efficacy of camptothecins against human prostate carcinoma models, in spite of p53 alterations. Although p53 status could influence DNA damage and cell cycle checkpoints, p53 mutation was not a determinant of resistance. The results support that, in addition to the extent and persistence of topoisomerase I-mediated DNA damage, cell cycle checkpoints and DNA damage signaling pathways are critical determinants of tumor responsiveness to camptothecins. A role of cell cycle checkpoints activated by DNA damage in cell response is supported by the modulation of transcriptional profile.

Original languageEnglish
Pages (from-to)1281-1294
Number of pages14
JournalBiochemical Pharmacology
Volume65
Issue number8
DOIs
Publication statusPublished - Apr 15 2003

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Camptothecin
Refractory materials
Prostate
DNA Damage
Hormones
Carcinoma
DNA
Cell Cycle Checkpoints
Cells
Apoptosis
Topotecan
Tumors
Cytostatic Agents
Pharmaceutical Preparations
S Phase Cell Cycle Checkpoints
Chemical activation
Lead compounds
Neoplasms
Type I DNA Topoisomerase
Critical Pathways

Keywords

  • Antitumor activity
  • Apoptosis
  • Camptothecins
  • Cytotoxicity
  • Prostate carcinoma
  • Xenografts

ASJC Scopus subject areas

  • Pharmacology

Cite this

Cellular bases of the antitumor activity of a 7-substituted camptothecin in hormone-refractory human prostate carcinoma models. / Zuco, Valentina; Supino, Rosanna; De Cesare, Michelandrea; Carenini, Nives; Perego, Paola; Gatti, Laura; Pratesi, Graziella; Pisano, Claudio; Martinelli, Roberta; Bucci, Federica; Zanier, Romina; Carminati, Paolo; Zunino, Franco.

In: Biochemical Pharmacology, Vol. 65, No. 8, 15.04.2003, p. 1281-1294.

Research output: Contribution to journalArticle

Zuco, V, Supino, R, De Cesare, M, Carenini, N, Perego, P, Gatti, L, Pratesi, G, Pisano, C, Martinelli, R, Bucci, F, Zanier, R, Carminati, P & Zunino, F 2003, 'Cellular bases of the antitumor activity of a 7-substituted camptothecin in hormone-refractory human prostate carcinoma models', Biochemical Pharmacology, vol. 65, no. 8, pp. 1281-1294. https://doi.org/10.1016/S0006-2952(03)00079-0
Zuco, Valentina ; Supino, Rosanna ; De Cesare, Michelandrea ; Carenini, Nives ; Perego, Paola ; Gatti, Laura ; Pratesi, Graziella ; Pisano, Claudio ; Martinelli, Roberta ; Bucci, Federica ; Zanier, Romina ; Carminati, Paolo ; Zunino, Franco. / Cellular bases of the antitumor activity of a 7-substituted camptothecin in hormone-refractory human prostate carcinoma models. In: Biochemical Pharmacology. 2003 ; Vol. 65, No. 8. pp. 1281-1294.
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