Dose-Finding and Pharmacokinetic Study of Cisplatin, Gemcitabine, and SU5416 in Patients With Solid Tumors

Kuenen, B.; Rosen, Lee S.; Smit, Egbert F.; Parson, M.; Levi, Marcel; Ruijter, Rita; Huisman, Holger; Kedde, Marc A.; Noordhuis, Paul; Vijgh, W.J.F. van der; Peters, Godefridus J.; Cropp, G.; Scigalla, P.; Hoekman, K.; Pinedo, H.M.; Giaccone, Giuseppe

doi:10.1200/jco.20.6.1657

Cited by 203 publications

(116 citation statements)

References 48 publications

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“…These data suggest that differences between the dividing tumor-associated endothelial cells and quiescent endothelial cells provide an opportunity for selective therapeutic intervention. However, in clinical trials with agents that target VEGF, hemorrhage and thrombosis have been observed as complications that may have been due in part to disruption of the normal vascular integrity (8). Furthermore, although our data with ZD6474 suggest that the quiescent vasculature of the lung may not be targeted, the interface between normal lung and tumor vasculature may be targeted.…”

Section: Discussioncontrasting

confidence: 43%

“…Bevacizumab, a humanized antibody against VEGF, has shown great promise and improved survival for patients with metastatic colorectal or lung cancer when used in combination with chemotherapy (6,7). However, although survival was improved in these studies, there remains an unmet need for improved efficacy, and clinical trials with VEGF inhibitors have been associated with thromboembolic and hemorrhagic complications (8).…”

Section: Introductionmentioning

confidence: 99%

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Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade

Wu¹,

Onn²,

Isobe³

et al. 2007

Molecular Cancer Therapeutics

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The outcome for patients with lung cancer has not changed significantly for more than two decades. Several studies show that the overexpression of vascular endothelial growth factor (VEGF)/vascular permeability factor and epidermal growth factor (EGF) and their receptors correlates with the clinical outcome for lung cancer patients. However, clinical trials of agents that target either of these pathways alone have been disappointing. We hypothesize that targeting both the tumor and its vasculature by simultaneously blocking the VEGFR and EGFR pathways will improve the treatment of locoregional lung cancer. Human lung cancer specimens were first examined for the activation of VEGF receptor 2 (VEGFR2) and EGF receptor (EGFR) for tumor and tumor-associated endothelial cells, and both were found to be activated. The effects of ZD6474 (ZACTIMA), a small-molecule inhibitor of VEGFR2 and EGFR tyrosine kinases, were then studied in vitro using human lung cancer and microvascular endothelial cells. In vitro, ZD6474 inhibited EGFR, VEGFR2, mitogenactivated protein kinase and Akt phosphorylation, EGF-and VEGF-induced proliferation, and endothelial cell tube formation and also induced apoptosis. ZD6474 was further studied in vivo using an orthotopic mouse model of nonsmall cell lung cancer using NCI-H441 human lung adenocarcinoma cells. The inhibition of both VEGFR2 and EGFR signaling pathways by ZD6474 resulted in profound antiangiogenic, antivascular, and antitumor effects. These results provide a basis for the development of clinical strategies for the combination of selective protein tyrosine kinase inhibitors that block both EGFR and VEGFR signaling as part of the management of locally advanced lung cancer. [Mol Cancer Ther 2007;6(2):471 -83]

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Section: Discussioncontrasting

confidence: 43%

Section: Introductionmentioning

confidence: 99%

Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade

Wu¹,

Onn²,

Isobe³

et al. 2007

Molecular Cancer Therapeutics

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show abstract

“…According to such reported values, a significant area of the synergistic interaction between these two drugs occurs in the range of clinically achievable concentrations. Importantly, a similar analysis also suggested that the predominant additive profile obtained from the combination of CIGB-300 plus cisplatin in cervical cancer cells occurs in a concentration range achievable in vivo for CIGB-300 (<30 µM) and cisplatin (<15 µM) (30,31).…”

Section: Discussionmentioning

confidence: 84%

Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

Perera

Toro

Gorovaya

et al. 2014

Molecular and Clinical Oncology

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Abstract. CIGB-300 is a novel clinical-stage synthetic peptide that impairs the casein kinase 2 (CK2)-mediated phosphorylation of B23/nucleophosmin in different experimental settings and cancer models. As a single agent, CIGB-300 induces apoptosis in vitro and in vivo and modulates an array of proteins that are mainly involved in drug resistance, cell proliferation and apoptosis, as determined by proteomic analysis. However, the clinical oncology practice and cumulative knowledge on tumor biology suggest that drug combinations are more likely to cope with tumor complexity compared to single agents. In this study, we investigated the antiproliferative effect of CIGB-300 when combined with different anticancer drugs, such as cisplatin (alkylating), paclitaxel (antimitotic), doxorubicin (antitopoisomerase II) or 5-fluorouracil (DNA/RNA antimetabolite) in cell lines derived from lung and cervical cancer. Of note, using a Latin square design and subsequent analysis by CalcuSyn software, we observed that paclitaxel and cisplatin exhibited the best synergistic/additive profile when combined with CIGB-300, according to the combination and dose reduction indices. Such therapeutically favorable profiles may be explained by a direct cytotoxic effect and also by the observed cell cycle impairment following incubation of tumor cells with selected drug combinations. Importantly, on in vivo dose-finding schedules in human cervical tumors xenografted in nude mice, we observed that concomitant administration of CIGB-300 and cisplatin increased mice survival compared to single-agent treatment. Collectively, these findings provide a rationale for combining the anti-CK2 CIGB-300 peptide with currently available anticancer agents in the clinical setting and indicate platins and taxanes as compounds with major perspectives.

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“…Although some clinical activity was recorded, and DEMRI analysis revealed a reduction in tumour vascular permeability, biological activity could not be demonstrated by means of consistent changes in the serum markers of endothelial cell proliferation. In phase I and II combination trials, SU5416 could be given safely in combination with 5-FU and leucovorin, but combining SU5416 with cisplatinum and gemcitabine yielded an unexpectedly high number of severe thromboembolic complications, leading to premature closing of the study (Kuenen et al, 2002a). Randomised phase III studies of SU5416 with 5-FU/ leucovorin and 5-FU/leucovorin/irinotecan in patients with metastatic colorectal carcinoma failed to show a survival benefit of the SU5416 containing regimens, resulting in the cessation of further development of this compound.…”

Section: Vegf Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

Eskens

2004

Br J Cancer

180

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Angiogenesis is crucial for tumour growth and the formation of metastases. Various classes of angiogenesis inhibitors that are each able to inhibit one of the various steps of this complex process can be distinguished. Results from clinical studies with these agents are summarised. In general, it has been shown that most angiogenesis inhibitors can be safely administered, but that tumour regressions are rare. Combining angiogenesis inhibitors with cytotoxic chemotherapy can enhance anticancer activity. Recently, some promising data with regard to clinical efficacy have been presented. While performing clinical studies with angiogenesis inhibitors, defining biological activity is crucial, but thus far no validated techniques are available. It is conceivable that in the near future various classes of angiogenesis inhibitors will be combined in an attempt to further improve antiangiogenic and anticancer activity.

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Dose-Finding and Pharmacokinetic Study of Cisplatin, Gemcitabine, and SU5416 in Patients With Solid Tumors

Abstract: The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.

Cited by 203 publications

References 48 publications

Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade

Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade

Synergistic interactions of the anti-casein kinase 2 CIGB-300 peptide and chemotherapeutic agents in lung and cervical preclinical cancer models

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

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