Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors

Vogt, Thomas; Hafner, Christian; Bross, K. J.; Bataille, Frauke; Jauch, Karl‐Walter; Berand, Anna; Landthaler, Míchael; Andreesen, Reinhard; Reichle, Albrecht

doi:10.1002/cncr.11775

Cited by 135 publications

(104 citation statements)

References 27 publications

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“…The novelty of our study combines metronomic chemotherapy with an anti-angiogenic agent in the clinical setting. There are few published clinical trials using such a combination, mostly phase I-II or abstracts [32][33][34][35][36][37][38][39]. In contrast to our study which showed benefit of docetaxel with thalidomide in solid tumors, Colleoni found that the addition of thalidomide to metronomic chemotherapy in advanced breast cancer patients did not improve the response rate compared to chemotherapy alone [40].…”

Section: Discussioncontrasting

confidence: 97%

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

et al. 2008

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Summary Purpose: Pre-clinical models have demonstrated the benefit of metronomic schedules of cytotoxic chemotherapy combined with anti-angiogenic compounds. This trial was undertaken to determine the toxicity of a low dose regimen using docetaxel and thalidomide. Patients and Methods: Patients with advanced solid tumors were enrolled. Thalidomide 100mg twice daily was given with escalating doses of docetaxel from 10 to 30mg/m 2 /week. One cycle consisted of 12 consecutive weeks of therapy. The maximal tolerated dose (MTD) was defined as the dose of thalidomide along with docetaxel that caused ≤grade 1 non-hematologic or ≤grade 2 hematologic toxicity for cycle one. Results: Twenty-six patients were enrolled. Doselimiting toxicities (DLTs) were bradycardia, fatigue, fever, hyperbilirubinemia, leukopenia, myocardial infarction, and neutropenia. Prolonged freedom from disease progression was observed in 44.4% of the evaluable patients. Conclusions: This anti-angiogenic regimen was well tolerated and demonstrated clinical benefit. The recommended phase II dosing schedule is thalidomide 100mg twice daily with docetaxel 25mg/m 2 /week.

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Section: Discussioncontrasting

confidence: 97%

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

et al. 2008

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“…Although in preclinical studies TZD showed antiproliferative, pro-apoptotic, and differentiating effects, their use in clinical trials planned for the treatment of limited cohorts of patients affected by different types of solid tumors gave controversial and not encouraging results (Demetri et al 1999, Debrock et al 2003, Vogt et al 2003, Reichle et al 2004, Smith et al 2004, Yee et al 2007, Read et al 2008. Indeed, only a few studies found TZD to exert some positive therapeutic effect, particularly if combined with chemotherapic and angiostatic drugs (Vogt et al 2003, Reichle et al 2004.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, only a few studies found TZD to exert some positive therapeutic effect, particularly if combined with chemotherapic and angiostatic drugs (Vogt et al 2003, Reichle et al 2004. This is of particular notice, since RGZ has been demonstrated to inhibit primary tumor growth and metastasis in different xenograft tumors through suppression of angiogenesis (Panigrahy et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model

Luconi¹,

Mangoni²,

Gelmini³

et al. 2010

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare aggressive tumor with a poor prognosis. The lack of a specific and effective medical treatment is due to the poor knowledge of the mechanisms underlying tumor growth. Research on potential drugs able to specifically interfere with tumor proliferation is essential to develop more efficacious therapies. We evaluated for the first time the in vivo effect of rosiglitazone (RGZ), an anti-diabetic drug with in vitro anti-tumor properties, on ACC proliferation in a xenograft model obtained by s.c. injection of human ACC H295R cells in athymic mice. When the tumor size reached 5 mm, animals were allocated to 5 mg/kg RGZ-or water-treated groups. Tumor volume was measured twice a week. A significant reduction of tumor growth in RGZ versus control (control) group was observed and was already maximal following 17 day treatment (1KT/CZ75.4% (43.7-93.8%)). After 31 days of treatment, mice were killed and tumor analyzed. Tumor histological evaluation revealed characteristics of invasiveness, richness in small vessels and mitotic figures in control group, while RGZ group tumors presented non infiltrating borders, few vessels, and many apoptotic bodies. Tumor immunohistochemistry showed that Ki-67 was reduced in RGZ versus control group. Quantitative real-time RT-PCR demonstrated a significant reduction in the expression of angiogenic (VEGF), vascular (CD31), proliferation (BMI-1), and anti-apoptotic (Bcl-2) genes in RGZ versus control group tumors. The same inhibitory effects were confirmed in in vitro RGZ-treated H295R. Our findings support and expand the role of RGZ in controlling ACC proliferation and angiogenesis in vivo and in vitro.

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“…Antiangiogenic properties for Tzds and PPARg agonists have been described in preclinical models (Xin et al, 1999;Panigrahy et al, 2002;Margeli et al, 2003) and a clinical trial (Vogt et al, 2003). These effects may be mediated through both PPARg-dependent and -independent pathways depending upon concentration of PPARg agonist and tumor cell type.…”

Section: Discussionmentioning

confidence: 99%

Novel high-affinity PPARγ agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1

et al. 2005

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Peroxisomeproliferator-activated receptor gamma (PPARc) agonists demonstrate antitumor activity likely through transactivating genes that regulate cell proliferation, apoptosis, and differentiation. The PAX8/PPARc fusion oncogene, which is common in human follicular thyroid carcinomas appears to act via dominant negative suppression of wild-type PPARc, suggesting that it may be a tumor suppressor gene in thyroid cells. We have identified a novel high-affinity PPARc agonist (RS5444) that is dependent upon PPARc for its biological activity. This is the first report of this molecule and its antitumor activity. In vitro, the IC 50 for growth inhibition is B0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited threeto fourfold in nude mice. siRNA against PPARc and a pharmacological antagonist demonstrated that functional PPARc was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21 WAF1/CIP1 . Silencing p21 WAF1/CIP1 rendered cells insensitive to RS5444. RS5444 plus paclitaxel demonstrated additive antiproliferative activity in cell culture and minimal ATC tumor growth in vivo. RS5444 did not induce apoptosis but combined with paclitaxel, doubled the apoptotic index compared to that of paclitaxel. Our data indicate that functional PPARc is a molecular target for therapy in ATC. We demonstrated that RS5444, a thiazolidinedione (Tzd) derivative, alone or in combination with paclitaxel, may provide therapeutic benefit to patients diagnosed with ATC.

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Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors

Cited by 135 publications

References 27 publications

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model

Novel high-affinity PPARγ agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1

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