Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice

Hanahan, Douglas; Bergers, Gabriele; Bergsland, Emily K.

doi:10.1172/jci9872

Cited by 761 publications

(524 citation statements)

References 17 publications

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“…27 This combination of metronomically dosed classic cytotoxic drugs with approved antiangiogenetic and biomodulating drugs has been suggested as a promising new tool in the treatment of patients with malignant disease. 28 Indeed, 3 of 6 patients (50%) responded with a CR (from 6 months to Ն 15 months) or an overall response (Ն 7 months). In 1 patient who had an extended angiosarcoma of the facial skin, a response to therapy was observed after only 14 days and was confirmed by histopathologic investigation.…”

Section: Discussionmentioning

confidence: 95%

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

Vogt

Hafner

Bross

et al. 2003

Cancer

135

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The processing–property relationship of a model cryogenically mechanically alloyed polymer–polymer system [polycarbonate (PC) and poly(aryl ether ether ketone) (PEEK)] was investigated. PC and PEEK powders were cryogenically mechanically alloyed for 10 h, and the resulting two‐phase powder particles were processed into testable coupons with a miniature ram‐injection molder. The bulk mechanical properties of the coupons made from the mechanically alloyed powders and nonmechanically alloyed powders were investigated as a function of mechanical alloying and injection‐molding parameters. The injection‐molded coupons were mechanically tested in the three‐point‐bending mode. The results demonstrated that no measurable improvement was achieved in the energy to break, strain at failure, or failure strength in the coupons made from the mechanically alloyed materials in comparison with those of the coupons made from the nonmechanically alloyed powders. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 1196–1202, 2003

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Section: Discussionmentioning

confidence: 95%

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

Vogt

Hafner

Bross

et al. 2003

Cancer

135

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“…It seems likely that such property, in addition to the unique ability to inhibit endothelial cell motility (Taraboletti et al, 2002), might contribute to the antitumour effect of IDN 5390 in vivo. Moreover, prolonged chronic treatment schedules have been reported as the most suitable for exploiting the antiangiogenic effect of cytotoxic drugs in in vivo systems (Browder et al, 2000;Hanahan et al, 2000;Klement et al, 2000). Preclinical and clinical experiences with PTX support the hypothesis ) and such schedule resulted as the best one for the antitumour efficacy of IDN 5390.…”

Section: Discussionmentioning

confidence: 98%

“…In order to target preferentially endothelial cells in in vivo models, a dosing schedule of the drug by short intervals and no interruption has been indicated as effective, in contrast to conventional schedules (i.e. maximum tolerated doses with extended resting periods) (Hanahan et al, 2000). By delivering conventional agents according to such 'an antiangiogenic schedule', a strong antitumour efficacy was achieved, even against chemoresistant tumours (Browder et al, 2000;Klement et al, 2000).…”

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confidence: 99%

IDN 5390: an oral taxane candidate for protracted treatment schedules

et al. 2003

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The recognition of the antiangiogenic properties of taxanes provides a basis for novel therapeutic approaches. A prolonged exposure to low drug concentrations has been proposed to be the most suitable approach to exploit the antiangiogenic potential of cytotoxic agents. Such schedule is required to target preferentially slowly dividing endothelial cells. The protracted use of taxanes could benefit from the availability of a taxane endowed with a favourable tolerability profile. Among compounds of a novel series of C-seco taxanes, IDN 5390 was originally selected on the basis of its potent antimotility activity and poor cytotoxicity on endothelial cells. The aim of the study was to investigate the preclinical pharmacologic profile of IDN 5390 in a variety of human tumour xenografts, including ovarian and colon carcinoma and a glioblastoma. IDN 5390, delivered by s.c. injection, daily for 5 days per week, exhibited a high activity against all tumours investigated (tumour growth inhibition was always 485%) in the range of well-tolerated doses. The maximum tolerated dose/injection (MTD), with no signs of systemic or local vesicant toxicity, was 120 mg kg À1 . In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD ¼ 10 mg kg À1 ). Considering the remarkable efficacy of IDN 5390 delivered s.c. by protracted treatment schedule, the oral route of administration was further investigated, as the most suitable for daily treatment. Indeed, a good bioavailability of oral IDN 5390 was found. Oral IDN 5390 maintained a substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency with respect to s.c. administration. In conclusion, the therapeutic advantages of IDN 5390, over paclitaxel, in protracted daily treatment schedules are represented by the oral efficacy and the high tolerability, which are favourable features to exploit the antiangiogenic potential and to design combinations with other effective agents.

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“…This suggests that to obtain the best results with anti-angiogenic drugs they will need to be used in conjunction with cytotoxic agents. Support for this concept has emerged from studies in which chemotherapeutic agents are administered in a metronomic low-dose schedule in an attempt to combine their anti-proliferative and anti-angiogenic activities (Vacca et al, 1999;Hanahan et al, 2000). Over the last decade there has been considerable interest in the natural oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2, Figure 1, 1) as a potential drug for cancer therapy (Seegers et al, 1989;Fotsis et al, 1994;Klauber et al, 1997;Brem, 1998;Zhu and Conney, 1998a, b;Lakhani et al, 2003;Dahut et al, 2006).…”

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confidence: 99%

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

et al. 2007

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Drugs that inhibit growth of tumours and their blood supply could have considerable therapeutic potential. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE) has been shown to inhibit the proliferation of MCF-7 (ER+) breast cancer cells and angiogenesis in vitro. 2-MeOE2bisMATE and its analogue, 17-Cym-2-MeOE2MATE, were investigated for their ability to inhibit in vivo angiogenesis and tumour growth. The mouse Matrigel plug assay for angiogenesis was used to investigate the effect of compounds on neovascularisation and was quantified using a FITC-dextran injection technique. Nude mice bearing tumours derived from MCF-7 cells were used to assess efficacy on tumour growth. Tumour sections were stained for VEGFR-2 and Ki67 to assess tumour angiogenesis and cell proliferation respectively. Matrigel plugs supplemented with basic fibroblast growth factor resulted in increased neovascularisation over 7 days. Oral administration of 2-MeOE2bisMATE for 7 days at 10 or 50 mg kg À1 significantly reduced neovascularisation to or below control levels respectively. 17-Cym-2-MeOE2MATE at 20 mg kg À1 was equally effective. 2-MeOE2bisMATE, dosed daily for 21 days, caused a 52% reduction in tumour growth at 5 mg kg À1 and 38% regression at 20 mg kg À1 . 17-Cym-2-MeOE2MATE (20 mg kg À1 ) reduced tumour growth by 92%. Immunohistochemistry revealed a reduction in angiogenesis and proliferation. Matrigel plug and tumour imaging after FITC-dextran injection indicated that 2-MeOE2bisMATE caused a marked disruption of vasculature. These sulphamoylated oestrogen derivatives have been shown to be potent inhibitors of angiogenesis in vivo. This, together with their ability to inhibit tumour growth, indicates the potential of this new class of drugs for further development for cancer therapy.

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Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice

Cited by 761 publications

References 17 publications

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

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

IDN 5390: an oral taxane candidate for protracted treatment schedules

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

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