Home > Uncategorized > Amino Bisphosphonates as Anti-Cancers

Amino Bisphosphonates as Anti-Cancers

The use of bisphosphonates (eg Aredia, Zometa, Clodronate) for cancer is not new and is not considered off-label, so why this blog? Well, these agents are only applied narrowly and used palliatively in most cases, ie only in certain cancers (notably myeloma, breast, prostate and more recently lung cancers) and only when there is bone metastases.  I have recently discussed the potential for adjuvant use of Clodronate in breast cancer, but I will share here some of the very exciting recent discoveries with newer generation bisphosphonates [so-caled amino bisphosphonates or nitrogen containing bisphosphonates “NBPs”, namely Aredia (pamidronate disodium) Zometa (zoledronic acid) Fosamax (alendronate) Actonel (risedronate) and Boniva (ibandronate)] as direct anti-cancers, ie the off-label potential to apply the newer generation NBPs in a combinatorial manner in the treatment of cancers.  So, where as it was originally and previously thought that bisphosphonates are useful in bone metastases because of the ability of these agents to inhibit bone resorption, newer understanding leads us to knowledge that such agents are really direct anti-cancers as well.  Without elaborating on the complex biochemical and molecular pathways (See diagram below, e.g. NBPs are thought to inhibit farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway,  in turn inhibiting the prenylation of small G-proteins such as Ras, Rap1, Rho and Rab, reduces the signals they mediate, and thereby prevents the growth, adhesion/spreading, and invasion of cancer cells) which have been extenstively reviewed, suffice it to say that NBPs cause direct cell cycle disruption and induce cancer cell death (so-called apoptosis), and this direct apoptotic effect of NBPs such as Zometa has now been reported in breast, prostate, myeloma, leukemia, colon cancers. Moreover, NBPs also independently inhibit cancer cell invasiveness, and exert anti-angiogenic effects as well via a variety of potential mechanisms.

Targets and Modes of Action of NBPs against Cancer (courtesy Caraglia M, et al. Endocrine-Related Cancer (2006) 13 p.14, Fig 2)

Now, back to the clinic.  With all the direct anti-cancer effects of the NBPs, we should then see some survival advantages of patients treated with Zometa or Aredia, but how come that hasn’t been widely reported and only noted in a subset of Zometa treated myeloma patients?  It seems like the problem is with the pharmacokinetics of the drugs themselves.  It turns out that not only are the half-lives of the drugs are very short in the blood ( no more than an hour or two), the maximum concentration achieved is also up to 100 fold less than what was demonstrated to cause cancer apoptosis (self-destruction) in the test tube experiments, although concentrations are adequate for anti-invasive effects.  These drugs tend to concentrate in the bones though, which explains why they are effective for controlling cancer metastatic to the bone.   However, all is not loss: it turns out that it is possible to manipulate the drugs to bring out its anticancer effects via pharmacological manipulations such as encapsulating the NBPs in liposomes and exploiting the NBP’s synergisms with other agents.

NBPs have been reported to be synergistic with various cytotoxic agents, cox-2 inhibitors, imatinib, bortezomib, rapamycin, ATRA (retinoic acid), thalidomide, histone deacetylase inhibitors (HDACs), and interferon beta on growth ihibition.

Perhaps most exciting is the recent finding that NBPs have immunomodulating properties, specifically by stimulating and expanding cytotoxic gammadelta T lymphocytes (See separate blog on this topic). There are very exciting recent reports of NBPs combined use with low dose Interleukin 2 (IL-2) to induce gammadelta T cells as immuotherapy against a variety of cancers.

My Take

NBPs are already in common use, and are quite non-toxic.  I think its use as a direct anticancer can be broadened to more cancer types as primary treatment used in a combinatorial manner if the latest research on gammadelta cell therapy (See my blog on this) is confirmed and its combined use with other potentially synergistic agents should be actively explored.  Based on principles of molecular action, I suspect that MMP inhibitors such as the tetracyclines and HMG Co-A reuctase inhitors (so-called “statins”, see separate blog on statins for cancer) should be synergistic with NBPs as well.  Baulch-Brown from Australia already demonstrated Zometa synergism with Lescol (Fluvastatin) against myeloma in vitro ( Leuk Res. 2007 Mar;31(3):341-52), and similar results were obtained with Zocor by a German group (Anticancer Drugs. 2006 Jul;17(6):621-9). In the future, we may look forward to new agents such as BPH-715 which is 200x more potent as an anti-cancer than current NBPs.  As to the current choice of NBP, current research seems to point to Zometa as being more powerful but it has to be administered parenterally.  Ibandronate (Boniva) is worth exploring for application because it can be given orally and has a better safety profile although less data is available but maybe I will explore this in a separate blog soon!

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