Phase Ι trial of weekly Docetaxel and daily Temozolomide in patients with metastatic disease

Tamaskar, Ila; Mekhail, Tarek; Dreicer, Robert; Olencki, Thomas; Roman, Sabine; Elson, Paul; Bukowski, Ronald M.

doi:10.1007/s10637-008-9153-0

Cited by 10 publications

(7 citation statements)

References 24 publications

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“…This TMZ suspension could be easily administered via a nebuliser in NSCLC patients and in patients with pulmonary metastases. TMZ is currently undergoing a large number of clinical trials (Lefranc et al, 2007), including trials with NSCLC patients (Choong et al, 2006;Tamaskar et al, 2008;Kouroussis et al, 2009), and its therapeutic benefits have been demonstrated in cancers associated with extremely poor prognoses, such as glioblastomas (Lefranc et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…TMZ is active against cancers associated with extremely poor prognoses, such as glioblastomas and melanomas (Lefranc et al, 2007). TMZ has recently been assayed in various clinical trials relating to lung cancer patients (Choong et al, 2006;Tamaskar et al, 2008;Kouroussis et al, 2009). Systemic longterm TMZ administration can lead to hematological toxicities in cancer patients (Dario and Tomei, 2006;Gerber et al, 2007), but the TMZ delivery system that we propose here could lower the TMZ-associated toxicity found with systemic TMZ delivery, while maintaining anticancer activity.…”

Section: Introductionmentioning

confidence: 98%

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In vivo assessment of temozolomide local delivery for lung cancer inhalation therapy

Wauthoz

Deleuze

Hecq

et al. 2010

European Journal of Pharmaceutical Sciences

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The aim of this study was to compare the efficacy of local drug delivery by inhalation to intravenous delivery in a B16F10 melanoma metastatic lung model. Temozolomide was formulated as a suspension, which was elaborated and evaluated in terms of particle size, shape and agglomeration. An endotracheal administration device was used to aerosolise the suspension. This mode of delivery was evaluated at different temozolomide concentrations and was optimized for the uniformity of delivered dose, the droplet size distribution and the distribution of droplets in vivo. Of the particles in the stabilised suspension, 79% were compatible with the human respirable size range, and this formulation retained 100% in vitro anticancer activity as compared to temozolomide alone in three distinct cancer cell lines. The pulmonary delivery device provided good reproducibility in terms of both the dose delivered and the droplet size distribution. Most of the lung tissues that were exposed to aerosol droplets contained the particles, as revealed by fluorescent microscopy techniques. The global in vivo antitumour activity of the inhaled temozolomide provided a median survival period similar to that for intravenous temozolomide delivery, and three out of 27 mice (11%) survived with almost complete eradication of the lung tumours. The present study thus shows that inhalation of a simple liquid formulation is well tolerated and active against a very biologically aggressive mouse melanoma pulmonary pseudo-metastatic model. This inhalation delivery could be used to deliver other types of anticancer drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

In vivo assessment of temozolomide local delivery for lung cancer inhalation therapy

Wauthoz

Deleuze

Hecq

et al. 2010

European Journal of Pharmaceutical Sciences

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“…Temozolomide has demonstrated antitumour activity against a broad range of tumour types, including malignant glioma, melanoma, NSCLC and carcinoma of the ovary and colon. In particular in the case of NSCLC, recent studies demonstrated that the combination of docetatel and temozolomide was well tolerated [36] and that the continuous low daily dose of temozolomide was associated with minimal toxicity in patients with NSCLC who had previously failed at least one chemotherapy regimen [37]. Therefore, the combination of low daily doses of temozolomide-which could result in a significant depletion of MGMT and enhance clinical activity [7,[38][39][40], with other anticancer drugs was suggested as another salvage option for patients with advanced NSCLC [37].…”

Section: Discussionmentioning

confidence: 99%

Cell death induced by N-methyl-N-nitrosourea, a model SN1 methylating agent, in two lung cancer cell lines of human origin

et al. 2009

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New therapeutic approaches are needed for lung cancer, the leading cause of cancer death. Methylating agents constitute a widely used class of anticancer drugs, the effect of which on human non small cell lung cancer (NSCLC) has not been adequately studied. N-methyl-N-nitrosourea (MNU), a model S(N)1 methylating agent, induced cell death through a distinct mechanism in two human NSCLC cell lines studied, A549(p53(wt)) and H157(p53(null)). In A549(p53(wt)), MNU induced G2/M arrest, accompanied by cdc25A degradation, hnRNP B1 induction, hnRNP C1/C2 downregulation. Non-apoptotic cell death was confirmed by the lack of increase in the sub-G1 DNA content, Poly (ADP-ribose) polymerase cleavage and caspase-3, -7 activation. In H157(p53(null)), MNU induced apoptotic cell death, confirmed by cytofluorometry of DNA content and immunodetection of apoptotic markers, accompanied by overexpression of hnRNP B1 and C1/C2. Thus, the mechanism of the cell death induced by S(N)1 methylating agents is cell type-dependent and must be assessed prior treatment.

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“…8,9 Combinations of both types of chemotherapeutic drugs have been applied as standard treatment regimens for various tumor entities, however, frequently evoking myelosuppression as a doselimiting side effect. [10][11][12] Various attempts were shown for chemoprotection of HSCs by retroviral transfer of MDR1 or MGMT. Gammaretroviral transfer of MDR1 into murine HSCs resulted in efficient chemoprotection against paclitaxel 13 or taxol.…”

Section: Introductionmentioning

confidence: 99%

F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells

et al. 2012

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Chemoprotection of haematopoietic stem cells (HSCs) by gene therapeutic transfer of drug-resistance genes represents the encouraging approach to prevent myelosuppression, which is one of the most severe side effects in tumor therapy. Thus, we cloned and evaluated six different bicistronic lentiviral SIN vectors encoding two transgenes, MGMT P140K (an O 6 -benzylguanineresistant mutant of methylguanine-DNA methyltransferase) and MDR1 (multidrug resistance 1), using various linker sequences (IRESEMCV, IRESFMDV and 2A-element of FMDV (F2A)). Expression of both transgenes in HL-60 and in K562 cells was assayed by quantitative real-time PCR. Combination therapy with ACNU plus paclitaxel in HL-60 cells and with carmustin (BCNU) plus doxorubicin in K562 cells resulted in the most significant survival advantage of cells transduced with the lentiviral vector HR'SIN-MGMT P140K -F2A-MDR1 compared with untransduced cells. In human HSCs, overexpression of both transgenes by this vector also caused significantly increased survival and enrichment of transduced cells after treatment with BCNU plus doxorubicin or temozolomide plus paclitaxel. In summary, we could show significant chemoprotection by overexpression of MDR1 and MGMT P140K with a lentiviral vector using the F2A linker element in two different haematopoietic cell lines and in human primary HSCs with various combination regimens. Consequently, we are convinced that these in vitro investigations will help to improve combination chemotherapy regimens by reducing myelotoxic side effects and increasing the therapeutic efficiency.

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Phase Ι trial of weekly Docetaxel and daily Temozolomide in patients with metastatic disease

Abstract: The combination of docetaxel and temozolomide was well tolerated and these agents can be safely combined. For phase II trials, docetaxel 35 mg/ m(2) IV day 1, 8 and 15, and daily temozolomide at 100 mg/ m(2) day 1-21 are recommended.

Cited by 10 publications

References 24 publications

In vivo assessment of temozolomide local delivery for lung cancer inhalation therapy

In vivo assessment of temozolomide local delivery for lung cancer inhalation therapy

Cell death induced by N-methyl-N-nitrosourea, a model SN1 methylating agent, in two lung cancer cell lines of human origin

F2A sequence linking MGMTP140K and MDR1 in a bicistronic lentiviral vector enables efficient chemoprotection of haematopoietic stem cells

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