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Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.

Martin-Liberal J, Gil-Martín M, Sáinz-Jaspeado M, Gonzalo N, Rigo R, Colom H, Muñoz C, Tirado OM, García del Muro X - Br. J. Cancer (2014)

Bottom Line: Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis.Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed.A phase II study is currently ongoing.

View Article: PubMed Central - PubMed

Affiliation: The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.

ABSTRACT

Background: We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine.

Methods: Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m(-2) on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted.

Results: Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment.

Conclusions: Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m(-2). Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing.

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Related in: MedlinePlus

(A) Western blot cleaved caspase 3. The greatest cleavage of caspase 3 was achieved when treatment was administered in a sequential manner: first gemcitabine followed by sirolimus 24 h later. (B) Western blot pS6 and S6. The activation of S6 observed when cells were treated with gemcitabine alone was reversed with the addition of sirolimus. G=gemcitabine; S=sirolimus; V=control.
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fig2: (A) Western blot cleaved caspase 3. The greatest cleavage of caspase 3 was achieved when treatment was administered in a sequential manner: first gemcitabine followed by sirolimus 24 h later. (B) Western blot pS6 and S6. The activation of S6 observed when cells were treated with gemcitabine alone was reversed with the addition of sirolimus. G=gemcitabine; S=sirolimus; V=control.

Mentions: We used cleaved caspase 3 as apoptosis marker to assess the in vitro efficacy of the combination. Results showed that the greatest activation of apoptosis was achieved with the sequential treatment administering gemcitabine first followed by sirolimus 24 h later (Figure 2A).


Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.

Martin-Liberal J, Gil-Martín M, Sáinz-Jaspeado M, Gonzalo N, Rigo R, Colom H, Muñoz C, Tirado OM, García del Muro X - Br. J. Cancer (2014)

(A) Western blot cleaved caspase 3. The greatest cleavage of caspase 3 was achieved when treatment was administered in a sequential manner: first gemcitabine followed by sirolimus 24 h later. (B) Western blot pS6 and S6. The activation of S6 observed when cells were treated with gemcitabine alone was reversed with the addition of sirolimus. G=gemcitabine; S=sirolimus; V=control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150275&req=5

fig2: (A) Western blot cleaved caspase 3. The greatest cleavage of caspase 3 was achieved when treatment was administered in a sequential manner: first gemcitabine followed by sirolimus 24 h later. (B) Western blot pS6 and S6. The activation of S6 observed when cells were treated with gemcitabine alone was reversed with the addition of sirolimus. G=gemcitabine; S=sirolimus; V=control.
Mentions: We used cleaved caspase 3 as apoptosis marker to assess the in vitro efficacy of the combination. Results showed that the greatest activation of apoptosis was achieved with the sequential treatment administering gemcitabine first followed by sirolimus 24 h later (Figure 2A).

Bottom Line: Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis.Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed.A phase II study is currently ongoing.

View Article: PubMed Central - PubMed

Affiliation: The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.

ABSTRACT

Background: We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine.

Methods: Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m(-2) on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted.

Results: Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment.

Conclusions: Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m(-2). Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing.

Show MeSH
Related in: MedlinePlus