Metronomic trofosfamide inhibits progression of human lung cancer xenografts by exerting anti-angiogenic effects

Klink, Thorsten; Bela, C.; Stoelting, Stephanie; Peters, Stefan O.; Broll, R.; Wagner, Thomas

doi:10.1007/s00432-006-0112-x

Cited by 10 publications

(4 citation statements)

References 23 publications

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“…With respect to the antiangiogenic basis of administering chemotherapy in a low-dose frequent manner, a number of studies have shown that some of the endothelial cells of the tumor's expanding neovasculature undergo apoptosis as a result of exposure to metronomic chemotherapy(1, 2) which presumably leads to the reduction in microvessel density as reported in some studies(1, 10). In addition, proangiogenic/vasculogenic bone marrow-derived cells (CEPs) can be targeted by various metronomic chemotherapy regimens(11-14).…”

Section: Introductionmentioning

confidence: 99%

Low-Dose Metronomic Oral Dosing of a Prodrug of Gemcitabine (LY2334737) Causes Antitumor Effects in the Absence of Inhibition of Systemic Vasculogenesis

Francia

Shaked

Hashimoto

et al. 2012

Molecular Cancer Therapeutics

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Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low minimally toxic doses with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials, and is currently undergoing phase III trial evaluation. It is thought to cause anti-tumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow derived cells, including circulating endothelial progenitor cells (CEPs). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, anti angiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T cell responses, or by direct anti-tumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 (LY) in non tumor-bearing mice, and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6mg/kg/day) the schedules tested were devoid of toxicity and caused anti-tumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly metronomic LY administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts; and this effect coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant anti-tumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis.

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Section: Introductionmentioning

confidence: 99%

Low-Dose Metronomic Oral Dosing of a Prodrug of Gemcitabine (LY2334737) Causes Antitumor Effects in the Absence of Inhibition of Systemic Vasculogenesis

Francia

Shaked

Hashimoto

et al. 2012

Molecular Cancer Therapeutics

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“…As such, metronomic chemotherapy may possess several advantages over conventional chemotherapy, including delaying the onset of acquired drug resistance and reducing host toxicity. Two milestone studies by Browder et al (2000) and by Klement et al (2000) followed by several subsequent studies have illustrated the capacity of different cytotoxic agents to preferably target the endothelial cell compartment of tumors when lower doses were given more frequently (Shaked et al, 2005;Klink et al, 2006).…”

mentioning

confidence: 99%

Preclinical Pharmacokinetic and Pharmacodynamic Evaluation of Metronomic and Conventional Temozolomide Dosing Regimens

Zhou¹,

Guo²,

Wang³

et al. 2007

J Pharmacol Exp Ther

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Metronomic dosed (MD) chemotherapy as opposed to conventional dosed (CD) chemotherapy is considered an alternate strategy to target angiogenesis and limit host toxicity. Although this approach is promising, there has not been any attempt to define optimal metronomic dosing regimens by integrating pharmacokinetic (PK) with pharmacodynamic (PD) measurements. The aim of this study was to compare the pharmacokinetics and pharmacodynamics of temozolomide [TMZ, 8-carbamoyl-3-methylidazo(5,1-d)-1,2,3,5-terrazin-4(3H)-one] after MD and CD regimens. In vivo studies were carried out in xenografted athymic rats treated with either 18 mg/kg/day TMZ for 5 days or 3.23 mg/kg/day TMZ for 28 days. PK studies were performed on the first and last days of dosing. PD measurements consisted of gene and protein expression of various angiogenic markers, tumor size, tumor pH, and interstitial fluid pressure (IFP). The results demonstrated that the PK parameters (total clearance, volume of distribution, and tumor/plasma accumulation) were quite similar for MD and CD groups, consistent with the linear PK properties of TMZ. Both TMZ treatment schedules caused a significant decrease in IFP and tumor size compared with vehicle control treatment, demonstrating comparable effectiveness of MD and CD regimens. Using real-time polymerase chain reaction and Western blot analyses, some differences were noted in expression levels of vascular endothelial growth factor and hypoxia inducible factor-1␣, suggesting that the MD regimen may be superior to the CD regimen by preventing tumors from progressing to a proangiogenic state. In conclusion, several PK/PD factors contributing to the antitumor activity of the MD TMZ therapy have been identified and form a foundation for further investigations of low-dose TMZ regimens.

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“…The maximum tolerated dose (MTD) of trofosfamide in continuous oral application has been evaluated in pretreated patients with metastatic lung cancer and has been shown to be 125 mg/m 2 [18]. Increasing evidence supports the clinical efficacy of metronomic therapy for the treatment of breast [19,20] and lung cancer [17,21,22]. While intuitively there should be no disagreement with what constitutes a metronomic therapy, the doses used are empirical.…”

Section: Discussionmentioning

confidence: 99%

“…Trofosfamide has been used for decades in the treatment of a variety of malignant diseases. Apart from the cytotoxic effect of trofosfamide there is also a distinct anti-angiogenic effect, especially if the drug is administered in a metronomic fashion [17]. The maximum tolerated dose (MTD) of trofosfamide in continuous oral application has been evaluated in pretreated patients with metastatic lung cancer and has been shown to be 125 mg/m 2 [18].…”

Section: Discussionmentioning

confidence: 99%

A Pilot Study of Docetaxel and Trofosfamide as Second-Line ‘Metronomic’ Chemotherapy in the Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC)

Gorn¹,

Habermann

Thöm³

et al. 2008

Onkologie

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Background: The aim of this pilot study was to evaluate the efficacy and safety of a chemotherapy containing docetaxel and oral trofosfamide as a ‘metronomic’ secondline treatment of patients with metastatic non-small cell lung cancer (NSCLC). Patients and Methods: 21 patients with stage IV disease NSCLC who had progressed under first-line chemotherapy were enrolled. Previous chemotherapy was platinum-based in 15 patients (71.4%), whereas 6 patients (28.6%) had received platinum-free combination chemotherapy. Patients received docetaxel 25 mg/m² on days 1, 8, and 15 every 4 weeks plus trofosfamide 50 mg per day. Results: A total of 62 chemotherapy cycles were administered. The median number of cycles per patient was 3. The overall response rate to chemotherapy was 19%, median overall survival was 6.9 months, the median progression-free survival 2.9 months, the 1-year survival rate 28.6%, and the 2-year survival rate 7.1%. No grade IV toxicity was observed. Conclusions: Our results suggest that the combination of docetaxel and trofosfamide in a metronomic schedule is active and well tolerable as second-line therapy in patients with metastatic NSCLC. The concept of metronomic chemotherapy promises to be a valuable addition to the existing treatment options in NSCLC and warrants further investigation in phase III studies.

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Metronomic trofosfamide inhibits progression of human lung cancer xenografts by exerting anti-angiogenic effects

Cited by 10 publications

References 23 publications

Low-Dose Metronomic Oral Dosing of a Prodrug of Gemcitabine (LY2334737) Causes Antitumor Effects in the Absence of Inhibition of Systemic Vasculogenesis

Low-Dose Metronomic Oral Dosing of a Prodrug of Gemcitabine (LY2334737) Causes Antitumor Effects in the Absence of Inhibition of Systemic Vasculogenesis

Preclinical Pharmacokinetic and Pharmacodynamic Evaluation of Metronomic and Conventional Temozolomide Dosing Regimens

A Pilot Study of Docetaxel and Trofosfamide as Second-Line ‘Metronomic’ Chemotherapy in the Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC)

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Metronomic trofosfamide inhibits progression of human lung cancer xenografts by exerting anti-angiogenic effects

Cited by 10 publications

References 23 publications

Low-Dose Metronomic Oral Dosing of a Prodrug of Gemcitabine (LY2334737) Causes Antitumor Effects in the Absence of Inhibition of Systemic Vasculogenesis

Low-Dose Metronomic Oral Dosing of a Prodrug of Gemcitabine (LY2334737) Causes Antitumor Effects in the Absence of Inhibition of Systemic Vasculogenesis

Preclinical Pharmacokinetic and Pharmacodynamic Evaluation of Metronomic and Conventional Temozolomide Dosing Regimens

A Pilot Study of Docetaxel and Trofosfamide as Second-Line &lsquo;Metronomic&rsquo; Chemotherapy in the Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC)

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A Pilot Study of Docetaxel and Trofosfamide as Second-Line ‘Metronomic’ Chemotherapy in the Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC)