July 15 2009 post. A longtime myeloma list friend/blog reader, thanks!, sent me the link to a new “Blood” study (http://tinyurl.com/lkmrz5) on an antifungal substance called ciclopirox olamine, or CPX, which has been found to decrease cell growth and viability of malignant leukemia, myeloma, and solid tumor cell lines as well as primary AML patient samples at low micromolar concentrations that appear pharmacologically achievable. Furthermore, oral CPX decreased tumor weight and volume in 3 mouse models of leukemia by up to 65% compared to control without evidence of weight loss or gross organ toxicity. (hmmm, I am not entirely sure that I like the sound of ”gross organ toxicity”…)
But get this: oral CPX has the ability to target leukemia stem cells. It targets STEM cells. Yes, the bloody evil STEM CELLS! I had to read that part at least twice before it sank in. Well…well…and…WELL!
I don’t know much about this substance, except what I read in the abstract (for instance that it is also an iron chelator)…but a quick bit of online poking led me to a couple of interesting studies, such as http://tinyurl.com/mxn3be. Unfortunately, I had to stop doing more research on this topic and, in fact, don’t have the time right now (=I have a complicated legal translation to do, sigh and double-sigh!) to connect the dots that I feel are lying just beyond my reach…(of course, I could be entirely wrong about the existence of any dots…aaah, if only I had more time…)
Well, as soon as possible, I will ask Sherlock if she would kindly get me the full study…in the meantime, based on what the study abstract tells us, CPX sounds like a very promising substance, to say the least…! I mean, holy cats, let’s say that you have toenail fungus AND myeloma…well, with CPX you might be able to treat both conditions…what an amazing thought…!
Update. September 7 2009. Sherlock (grazie!) sent me the full ciclopirox olamine study that I posted about on July 15th (the nail fungus treatment, remember?). I will skip through it and provide only a few excerpts for discussion, trying not to repeat the information that is already in the abstract (http://tinyurl.com/lkmrz5).
One important statement is that CPX-induced cell death was dependent on chelation of intracellular iron and the inhibition of the iron-dependent enzyme ribonucleotide reductase (all we really need to know about ribonucleotide reductase, or RNR, is that it is an appealing target in cancer treatment. An RNR-inhibitor, such as CPX, is therefore one of the good guys, so to speak…).
Let’s see. A number of pages are devoted to material and methods…skip skip skip…let’s go to the study results. Aha…I had wondered how/why ciclopirox olamine had been chosen among a number of other off-patent drugs with previously unrecognized anti-cancer activity. The mystery was solved in the full study: a screening process identified CPX as a substance that inhibited the growth of leukemic cells that display features similar to leukemic stem cells.
CPX was also identified as a survivin-inhibitor. Survivin is a protein that is also a regulator of cell cycle and apoptosis, and cancer cells contain high levels of it (for more info, you can search my blog for “survivin”). CPX was found to decrease the levels of survivin in leukaemia, myeloma and solid tumour cells. So far, so good.
Remember reading about “gross organ toxicity” in the abstract? Well, that “gross” business puzzled me, so I looked it up and found that, in pathology, a gross examination of a specimen is an examination done with the bare eye…without the use of any instruments, such as a microscope. Ah. Okay. So, unless I am way off base, it appears that treatment with CPX causes no harm to any organs or loss of body weight…based on a “bare eye” examination. CPX did, however, decrease tumor weight and volume in 3 mouse models of leukemia by up to 65%. Great!
More good news: CPX reduced the viability of primary AML cells and inhibited engraftment of primary AML cells in NOD/SCID mouse models. Thus, CPX appears cytotoxic to leukemia stem cells. A killer of leukemic stem cells! Yeah!
Well, I don’t want to go into too much detail…for instance, I could provide you with a detailed description of how CPX binds intracellular iron in cancer cells or how the inhibition of ribonucleotide reductase is functionally important for the cytotoxic effects of CPX or how CPX sensitizes cells to cytarabine. But I won’t. Too much information could give me AND you a stomping headache!
Just one last thing. In the Discussion part, we can read that CPX could be advanced quickly into clinical trial for patients with refractory hematologic malignancies. However, due to possible differences in iron pools between species, toxicities of CPX not apparent in rodents and dogs may become evident in humans clinical trials. Alternatively, CPX may be less effective in patients who have been heavily transfused and have very high levels of iron stores.
The issue of toxicity is a serious one, of course, and the authors point out that the potential hematologic toxicity and its safety will have to be carefully evaluated in phase I clinical trials. Well, an interesting study, for sure…