Traditional chemotherapy kills tumour cells directly; some newer drugs work instead by cutting the tumour's blood supply. An innovative approach combines these strategies sequentially to pack a double whammy.
In 1971, Judah Folkman proposed that the progression of cancer might be halted by preventing tumours from recruiting new blood vessels (a process called angiogenesis) to provide them with oxygen and nutrients. Last year, this theory bore fruit with the approval by the US Food and Drug Administration of the first anti-angiogenic cancer treatment, Avastin (also known as bevacizumab)1. Sengupta and colleagues (page 568 of this issue)2 advance this concept by designing a drug-delivery vehicle that sequentially releases an anti-angiogenic drug and a traditional chemotherapeutic drug at high concentrations specifically into a tumour. They report that their strategy can slow tumour growth in mice more than can either drug alone or the two drugs delivered at the same time.
Traditional chemotherapeutic agents kill all rapidly growing cells in the body — both cancer cells and other cells that divide quickly (for example, blood, hair and cells lining the intestine). This leads to the distressing side effects of chemotherapy, and limits the practical dose and frequency of application of the drugs. One tactic to avoid these effects is to target the drug specifically to the tumour, and approaches being tested include the incorporation of drugs into materials or complexes that can either be placed in, or directed to, tumours3
A second issue, however, is that some tumours develop resistance to a particular drug, so efforts to identify targets that are not prone to developing resistance continue. Endothelial cells, which line blood vessels, may provide an attractive target, as they are thought to be genetically more stable than cancer cells and so less likely to develop mutations that might promote resistance. A number of drugs that kill endothelial cells or prevent their growth are proving effective in phase III clinical trials for treating colon, kidney and lung cancer, and gastrointestinal stromal tumours1,4,5,6. These drugs can be useful alone, but they are commonly combined with traditional chemotherapy to prevent blood-vessel growth while also killing cancerous cells.
Simultaneous delivery of chemotherapeutic and anti-angiogenic drugs is clearly beneficial, but because chemotherapy is blood-borne, shutting down the tumour's blood supply with anti-angiogenic drugs may decrease the delivery of drugs designed to kill the tumour cells. Sengupta et al.2 hypothesized that a more effective strategy would be to use a delivery vehicle that became concentrated in tumours before the vasculature shut down, and allowed the staged release of the two drugs. More specifically, the delivery of the anti-angiogenic factor could lead to a collapse of the vascular network and imprison the vehicle — still bearing its second payload of chemotherapeutic drug — in the tumour. The subsequent release of the latter drug within the tumour would kill the cancer cells.
The authors exploited the fact that the blood vessels of tumours are 'leaky'7, so tumour tissue can take up larger particles than can normal tissues, promoting selectivity. They created composite vehicle particles of 80–120 nm, consisting of a solid biodegradable polymer core surrounded by a lipid membrane (Fig. 1). The anti-angiogenic drug combretastatin was dissolved in the lipid layer, from which it rapidly escaped. This drug attacks the internal skeleton of cells, and quickly disrupts blood vessels. The chemotherapeutic drug doxorubicin was bound chemically to the inner core of the particle, and so was released more slowly as the bond holding the drug to the polymer broke down. Doxorubicin is a common chemotherapeutic agent, and its structure consists of chemical groups that are amenable to attachment to polymers.
Sengupta et al. examined the effects of the drugs on two types of tumour in mice, and showed that, unsurprisingly, either drug alone slowed tumour growth, and that when the drugs were delivered simultaneously there was an additive effect. Strikingly, however, the staged release of the two drugs using the new delivery vehicle improved the outcome still further — survival time increased from approximately 30 days when the drugs were delivered simultaneously to more than 60 days when they were released sequentially. The delivery vehicles tended to accumulate in the tumours, rather than in other body tissues, and the drugs they transported killed both endothelial and cancer cells.
The effect of the sequential delivery of these two drugs on tumour growth is dramatic, but we cannot assume a quick translation of these results to therapy for humans. The biological differences between mice and humans prevent direct comparison between the systems, and it will also be important to extend these studies to longer time periods. Moreover, it has been speculated that anti-angiogenic drugs may actually promote the spread of tumours to other tissues, owing to a complex feedback loop, although there is no evidence of this in humans8. It is promising, in this regard, that Sengupta and colleagues' system produced no increase in the expression of a factor (HIF-1α) that can link the low oxygen levels resulting from reduced blood flow with potential resistance to drug therapy and tumour invasiveness. Finally, in contrast to combretastatin, many anti-angiogenic drugs require prolonged tissue exposure to shut down the vasculature, and so may not be amenable to the particular approach described by Sengupta and colleagues.
The general concept of timing the availability of drugs aimed at specific stages or targets in cancer is widely applicable, however, and is consistent with similar efforts to promote blood-vessel formation in diseases involving insufficient blood flow9. Appropriate design of drugs will allow targeting of cancer cells or other specific cell types10, and the delivery device described by Sengupta et al. could readily be modified for this. It may also be necessary to target multiple aspects of angiogenesis, either by using several drugs or by using a drug that interferes with several pathways (for example, MAPK inhibitors)11, to prevent tumours from switching on alternative angiogenesis pathways. Ultimately, combining the development of advanced drug-delivery systems with the identification of early markers of cancer may allow early and highly effective intervention, and help to accomplish the US National Cancer Institute's stated goal of eliminating the suffering and death from cancer by 2015.
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