The dynamics of tumour-vasculature interaction suggests low-dose, time-dense anti-angiogenic schedulings.
OBJECTIVE
The administration schedule appears to be a particularly relevant factor in determining the effectiveness of an antiangiogenic drug. A better quantitative knowledge of the interactions between tumour growth and the development of its vasculature could help to design effective therapies.


METHODS
Biological and clinical inferences were derived from the analysis of a mathematical model proposed by Hahnfeldt et al. (1999), and some of its variants. In particular, we compared the effect of constant continuous infusion of an anti-angiogenic drug that induces vascular loss, to the effect of periodic, bolus-based therapy.


CONCLUSIONS
The role of drug elimination rate and of dose fractionation was investigated, and we show that different schedulings, guaranteeing the same mean value of drug concentration, may exhibit very different long-term responses according to their concentration vs. time profile. For a large class of tumour growth laws, the profiles that approach the constant one are the most effective. This behaviour appears to depend on the 'cooperativity' of the tumour-vasculature interaction and on the functional form of the relationship between tumour growth and vasculature extent. Moreover, we suggest that a therapy approaching constant drug infusion might be advantageous also in the case of cytostatic anti-angiogenic drugs.
d'Onofrio
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Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. alberto.donofrio@ifom-ieo-campus.it
Gandolfi
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Rocca
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D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000517:prevention & control*
D020533:Angiogenesis Inhibitors