Monday 17 November 2014

Bisphosphonates in non-bone tumours

Bisphosphonates are a class of bone-targeted drug that act to slow the turn-over of bone (bone resorption). These drugs, including zoledronate, ibandronate and others, are standard treatments for osteoporosis and other bone diseases. And, as I have mentioned previously on this blog they have increasingly found use in cancer treatment to help control bone-related problems - both from metastatic disease to the bone and in primary bone tumours. There is also increasing evidence that as well as controlling bone pain and reducing fractures, these drugs have some very positive effects on overall survival. For example there is now evidence that zoledronate (also called Zometa or zoledronic acid) gives a survival advantage even in early stage breast cancer. Now this is something of a surprise because the effects are there even when there are no bone metastases, so the drug must be acting on non-bone tumour tissue - how is this possible?

New light has been shed on the matter by some recent work that convincingly shows that zoledronic acid is taken up by cancer associated cells outside of bony metastases. Some clever lab work has shown that zoledronic acid attaches itself to tiny crystals of calcium (microcalcifications) outside of the bone. These microcalcifications are then eaten up by tumour associated macrophages, immune cells that actively encourage and support tumour growth. Once these macrophages have swallowed the microcalcifications with the zolderonic acid attached the drug can get to work and interfere with their function. In other words, the drug doesn't affect tumour cells directly, it affects the cells that provide some of the life-support that tumours require. The lab work on mice was also confirmed on a tumour sample from a breast cancer patient.

This is good news as having an understanding of the mechanics of zoledronic acid is an important addition to the clinical evidence of effectiveness and will hopefully persuade more clinicians that this is something that needs to be incorporated into standard clinical practice, particularly for breast cancer and other forms of the disease where these microcalcifications are common.

An interesting aside is that this study (abstract here) showed that the zoledronic acid accumulates very quickly into the area around the tumour due to the leaky blood vessels that feed the tumour. This means that the drug is targetted into the right environment very quickly. But it does make me wonder whether there's an opportunity here to improve the response by making those blood vessels even more leaky by the use of the drug nitroglycerin. If so then this is a cheap and non-toxic way of making sure that we maximise the therapeutic effect in patients.

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