Published data for this review were identified by searches of MEDLINE, CANCERLIT, and Dematel databases. MeSH terms used were ‘antiangiogenic cancer chemotherapy’, ‘cytotoxic agents’, ‘inhibitors of angiogenesis’, and ‘metronomic chemotherapy’. Additional references were selected from relevant articles. Only papers in English, published up to July 2001, were chosen.
ReviewMetronomic scheduling: the future of chemotherapy?
Section snippets
The angiogenesis–chemotherapy model
Angiogenesis is necessary to sustain the growth of both the primary tumour and the development of metastases.12 Therapeutic targeting of tumour angiogenesis was first proposed by Folkman 30 years ago, at a time when the molecular mechanisms underlying abnormal neovascularisation were unknown.14 Progress in our understanding of the cellular and molecular basis of this biological process allowed the identification of several molecular targets and different selective approaches for inhibiting
Experimental studies on the antiangiogenic activity of metronomic chemotherapy
O'Leary and colleagues24 found that camptothecin analogues, which target the enzyme topoisomerase I, also cause significant suppression of angiogenesis in an in vivo mouse corneal model, at a dose of 359 nmol/kg (210 mg/kg) delivered over 6 days. This frequency of treatment prevented tumour and endothelial cell regrowth, and was active against tumour microvasculature.
Clements and coworkers25 used low (nanomolar), noncytotoxic concentrations of camptothecin and topotecan (50 nmol) to confirm the
Metronomic versus dose-density scheduling
Proof of the concept of metronomic scheduling requires the development of appropriate intermediate surrogate markers, which can be monitored before and after therapy; any quantitative or qualitative changes in the proliferation of endothelial cells also needs to be monitored. The concept of ‘high-time’ chemotherapy, defined as the longest possible period of drug exposure at a given desired drug concentration, is very useful for long-term therapy, but requires careful assessment of the
Metronomic schedules of chemotherapy in combination with antiangiogenic inhibitors and other molecular-targeted treatments
Significant antiangiogenic and antitumour effects are unlikely to be achieved in the clinical setting with a single chemotherapeutic agent at metronomic doses. The ability of metronomic chemotherapy to block angiogenesis, compared with that of selective angiogenesis inhibitors, remains to be proven, at least in terms of effective prolongation of survival.
Pioneering studies by Kakeji and Teicher39 showed potentiation or synergism when angiogenesis inhibitors were combined with standard schedules
Clinical studies
There are currently no published clinical studies in which metronomic scheduling of chemotherapy was compared with conventional schedules, nor are there any that describe appropriate in vitro or in vivo methods of monitoring antiangiogenic activity. However, a few trials have involved metronomic-like chemotherapy schedules. For example, the phase I study by Retain and colleagues55 involved continuous infusion of low doses of vinblastine for up to 36 weeks. The researchers found that 0·7 mg/m2
Future directions
There are several theoretical advantages and opportunities to be explored with regard to metronomic chemotherapy in combination regimens (Table 3). However, these regimens also present potential problems and challenges in terms of appropriate experimental study design and clinical testing. First, combined metronomic chemotherapy regimens should be further tested in experimental studies, in orthotopic and metastatic tumour models, as suggested by Fidler and Ellis,4 before proceeding to clinical
Search strategy and selection criteria
References (68)
- et al.
Vasculature and microenvironmental gradients: the missing links in novel approaches to cancer therapy?
Adv Enzyme Regul
(1998) - et al.
Angiogenesis: pathological, prognostic, and growth-factor pathways and their link to trial design and anticancer drugs
Lancet Oncol
(2001) - et al.
Antiangiogenesis is produced by noncytotoxic doses of vinblastine.
Blood
(1999) - et al.
Taxol involution of collagen-induced arthritis: ultrastructural correlation with the inhibition of synovitis and neovascularization.
Clin Immunol Immunopathol
(1998) - et al.
Does an improved control of tumor growth require an anti-cancer therapy targeting both neoplastic and intratumoral endothelial cells?
Eur J Cancer
(1994) - et al.
Cyclooxygenase regulates angiogenesis induced by colon cancer cells.
Cell
(1998) - et al.
“Classical” CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer.
Eur J Cancer
(1991) - et al.
Implications of biochemical, cytokinetic, pharmacologic and toxicologic relationships in the design of optimal therapeutic schedules.
Cancer Chemother Rep
(1970) - et al.
Shifting the cancer paradigm: must we kill to cure?
J Clin Oncol
(1995) - et al.
Chemotherapeutic drugs: more really is not better.
Nat Med
(2000)
Pharmacogenetic applications of the Human Genome Project.
Nat Med
Clinical strategies for cancer treatment: the role of drugs
Antiangiogenic scheduling of lower dose cancer chemotherapy
Cancer J
Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for combination therapy.
Cancer Met Rev
Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents.
BioEssays
A cancer therapy resistant to resistance.
Nature
Tumor angiogenesis: past, present and the near future.
Carcinogenesis
The microenvironment of the tumour-host interface.
Nature
Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice.
J Clin Invest
Tumor angiogenesis: therapeutic implications.
N Engl J Med
The rationale and future potential of angiogenesis inhibitors in neoplasia.
Drugs
Genes expressed in human tumor endothelium.
Science
Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance.
Nature
Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer.
Cancer Res
Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity.
J Clin Invest
Vascular attack as a therapeutic strategy for cancer.
Cancer Metastasis Rev
Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphomas.
Cancer Res
Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool.
J Clin Oncol
Antiangiogenic effects of camptothecin analogues 9-amino-20(S)–camptothecin, topotecan, and CPT-11 studies in the mouse cornea model.
Clin Cancer Res
Antiangiogenic potential of camptothecin and topotecan.
Cancer Chemother Pharmacol
Synthetic analogues of fumagallin that inhibit angiogenesis and suppress tumour growth.
Nature
Purine analogue 6-methylmercaptopurine riboside inhibits early and late phases of the angiogenesis process.
Cancer Res
Role of interferons in the regulation of cell proliferation, differentiation, and development.
Mol Reprod Dev
Interferon-_-mediated downregulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule.
Clin Cancer Res
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