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01.09.2007 | Original Article

Preclinical antitumor activity of the oral platinum analog satraplatin

verfasst von: Katja Wosikowski, Lou Lamphere, Gerhard Unteregger, Volker Jung, Faith Kaplan, Jimmy P. Xu, Benno Rattel, Maureen Caligiuri

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2007

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Abstract

Purpose

Satraplatin is an orally available platinum analog. The purpose of this study was to better characterize satraplatin’s preclinical antitumor efficacy in a variety of sensitive and resistant human tumor cell lines and in a prostate cancer xenograft model and to evaluate the effect of satraplatin on PSA expression and/or secretion in a prostate cancer cell line.

Methods

Satraplatin and its primary metabolite JM-118 were preclinically tested for their cytotoxic activity in a range of cancer cells including: human prostate, those forming the NCI drug screening panel, and those resistant to anti-cancer drugs. Also, the antiproliferative efficacy of satraplatin was tested in vivo in a human prostate cancer model. The effect of satraplatin and JM-118 on PSA transcription was measured by quantitative real time PCR.

Results

Satraplatin and JM-118 inhibited in vitro and in vivo the growth of prostate cancer cells in a dose-dependent fashion. The IC₅₀ cytotoxicity values for satraplatin ranged from 1 to 3 μM for androgen-insensitive cells and was 11 μM for the androgen-sensitive cell line. Interestingly, JM-118 was up to 16-fold more potent than satraplatin. Oral administration of satraplatin to nude mouse PC-3 xenograft models inhibited the growth of these human tumors. Satraplatin had no direct effect on PSA transcription and the observed decrease in secreted PSA correlated with a decrease in cell number. When evaluated in the NCI drug-screening panel, satraplatin was most active in leukemia and small cell lung cancer cell lines.

Both satraplatin and JM-118 were tested on cells resistant to chemotherapeutic agents. Satraplatin and JM-118 were equally active in the cisplatin-resistant A129cp80 ovarian carcinoma cell line, with activity comparable to that observed in the parent line. Neither expression of MDR1, BCRP, MRP1, nor altered tubulin or topoisomerase I were found to mediate resistance to satraplatin or JM-118. Although these resistance mechanisms contribute to drug resistance for a number of chemotherapeutics, they do not appear to play a role in satraplatin resistance.

Conclusions

These results demonstrate that satraplatin and JM-118 have preclinical antitumor activity in human prostate cancer and other tumor types as well, including several cell lines displaying drug resistance to cisplatin, docetaxel and mitoxantrone. In addition, the results suggest that PSA should be further evaluated as a relevant marker of clinical response in patients with prostate cancer treated with satraplatin.

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Titel: Preclinical antitumor activity of the oral platinum analog satraplatin
verfasst von: Katja Wosikowski
Lou Lamphere
Gerhard Unteregger
Volker Jung
Faith Kaplan
Jimmy P. Xu
Benno Rattel
Maureen Caligiuri
Publikationsdatum: 01.09.2007
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2007
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-007-0502-z

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Preclinical antitumor activity of the oral platinum analog satraplatin

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Purpose

Methods

Results

Conclusions

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