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Chemotherapy

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NO-NSAIDs

Date: August 30, 2003

by Chaya Venkat

A New Class of Agents?

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The title of this article, "NO-NSAIDs" is not telling you to "Just say NO!!" to NSAIDs.

NSAIDs (non-steroidal anti-inflammatory drugs, best known example of which is plain old aspirin) have been used for many decades to reduce inflammation, and the pain associated with it. More recently, we have begun to understand the link between inflammation and cancer. Many of the pathways that contribute to inflammation are the same ones that also cause cancer cell proliferation, and prevent their programmed suicide (apoptosis). We have discussed the role of NSAIDs like aspirin, newer compounds like Celebrex, Vioxx, and R-Flurbiprofen, chemopreventive supplements such as green tea, resveratrol and curcumin, in their ability to suppress NF-kB activation, block some of the inflammatory pathways, as an approach to prevent and/or control cancer growth. You can look up some of my articles on these subjects, as well as John Perry's several excellent articles as well. I think the latest one I did on this subject was titled "How to keep the party going" or something to that effect, discussing the actions of a hypothetical Joe Patient after finishing his Rituxan monotherapy.

One of the issues with continuous and long term use of NSAIDs is the very real danger of irritation of the stomach lining, and potential for gastric ulcers. Drugs such as Celebrex and R-Flurbiprofen are supposed to get around that, but there are still mixed reports on their ability to protect the stomach lining.

Now comes a whole series of new drugs, called "NO-NSAIDs", or nitric oxide ("NO") donating NSAIDS. These are slightly new versions of all the NSAIDs we have heard of, "NO-aspirin", "NO-ibuprofen", "NO-Flurbiprofen", you name the NSAID, they have made a nitric oxide donating version of the molecule. Basically, in each case, a new nitrogen oxide releasing fragment has been added on to the standard version of the NSAID. Different formulations of the drugs have been tested for a variety of uses besides standard use as anti-inflammatory drugs.

The first abstract below compares standard aspirin versus NO-aspirin in terms of protecting the lining of the stomach, the original basis for the development of the NO-NSAIDs. So far, things are looking good. 

The second abstract goes for the big one, testing a variety of NO-NSAIDs against a whole series of cancer cell lines. In almost all the cases, "The potency of NO-NSAIDs was 11- to 6000-fold greater than that of their counterparts". The bottom line evaluation is quite bullish, "These results raise the possibility that NO-NSAIDs possess chemopreventive and/or chemotherapeutic activity against a wide variety of human cancers". 

Last but not least, the third abstract really got my attention, there appears to be a significant synergy between the effects of our beloved chemotherapy drug Fludarabine and NO-donating drugs such as NO-NSAIDs. To put this in a nutshell, in the presence of NO-donating drugs such as the NO-aspirin, a much smaller dose of Fludarabine is able to do the same job. Since there is a clearly established connection between toxicity of Fludarabine and the dosage level, this could be very good news for cancer patients. It is expected that the NO-NSAIDs themselves are non-toxic, and this abstract suggests that using them in conjunction with chemotherapy drugs such as Fludarabine can have real benefits of reduced toxicity and improved performance. 

I sum up my introduction of NO-NSAIDs with the last abstract, (by the way you can get the full article for free, if you are interested) that goes into some of the details of how nitric oxide influences various physiological functions. 

All in all, in my opinion this is an encouraging development that is worth watching. And one that you should discuss with your oncologist, if you are lucky enough to have a good relationship with yours, and he/she likes to hear about new developments. I do not know how hard it would be to get hold of NO-aspirin, especially if the request goes through official channels and your oncologist makes the request. Probably not too hard, but I may be wrong. If Fludarabine therapy is in your near future, you might be interested in checking this out. For many of you, the toxicity of chemotherapy is a real issue, and yet it is necessary to control the CLL. Here may be a partial solution around that particular Catch-22.

Here is an incomplete tabulation of NO-NSAID drugs in development:

Current Status of NO-releasing NSAIDs in Development
Company Sources
DRUG COMPANY STATUS
NO-aspirin NicOx Phase II @ 11/14/01
NO-diclofenac NicOx Pre-clinical
NO-naproxen Astra-Zeneca Phase II
NO-ketoprofen NicOx Pre-clinical
NO-ibuprofen NicOx Phase I
S-NO-diclofenac Nitromed Pre-clinical

NO is now recognized as an important modulator of an enormous number of physiological functions, not something you want to fool around with on a home-made clinical trial. I expect that it will be a number of years before any NO-release containing drug is commercially available, outside of clinical trials. It is an interesting development, and one worth watching, perhaps discussing with your healthcare providers. NOT one to try at home without adult supervision.

Abstracts

Eur J Med Chem. 2003 Apr;38(4):441-6.

Nitric oxide-donating non-steroidal anti-inflammatory drugs: the case of nitroderivatives of aspirin. 

Chiroli V, Benedini F, Ongini E, Del Soldato P. 

Nicox Research Institute, Via Ariosto 21, 20091 Bresso, Milan, Italy. 

Nitric oxide (NO) acts as a key signalling mechanism in a number of cells and tissues in the mammalian organism. Modulation of the biosynthesis of NO has emerged to be relevant to the treatment of a variety of human diseases. In the attempt to reduce the serious side effects of non-steroidal anti-inflammatory drugs (NSAIDs), especially in the gastrointestinal tract, a NO-releasing moiety has been linked to conventional NSAIDs. A prototypical example is that of NO-releasing derivatives of aspirin. Thanks to the cytoprotective action of NO such compounds do not produce gastric damage and are emerging as an interesting novel group of drugs for their unique pharmacological properties. 

PMID: 12750033
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J Pharmacol Exp Ther. 2002 Dec;303(3):1273-82.

Nitric Oxide-Donating Nonsteroidal Anti-Inflammatory Drugs Inhibit the Growth of Various Cultured Human Cancer Cells: Evidence of a Tissue Type-Independent Effect 

Khosrow Kashfi , Yassir Ryann, Leon L. Qiao, Jennie L. Williams , Jie Chen, Piero del Soldato, Frank Traganos and Basil Rigas 

American Health Foundation, Valhalla, New York (K.K., J.L.W., J.C., B.R.); Department of Physiology and Pharmacology, City University of New York Medical School, New York, New York (K.K.); Sarah C. Upham Division of Gastroenterology, New York Medical College, Valhalla, New York (Y.R., J.L.W., P.d.S., B.R.); University of Iowa Hospitals and Clinics, Iowa City, Iowa (L.L.Q.); and Brader Cancer Research Institute, Department of Medicine, New York Medical College, Valhalla, New York (F.T.) 

The novel nitric oxide (NO)-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs), which are safer than their NSAID counterparts, inhibit the growth of colon cancer cells with far greater potency than traditional NSAIDs. We examined whether NO-NSAIDs inhibit the growth of cancer cells arising from other human tissues. Human pancreatic, colon, prostate, lung, and tongue cancer cell lines were treated with NO-aspirin, -sulindac, -ibuprofen, and -indomethacin or their traditional counterparts. We determined IC50 values, cell proliferation, apoptosis, cell cycle, cyclooxygenase (COX) protein levels, and morphological changes (light and electron microscopy). All NO-NSAIDs inhibited the growth of all cancer cell lines studied. The potency of NO-NSAIDs was 11- to 6000-fold greater than that of their counterparts (except for the effect of sulindac on lung cancer cells). NO-aspirin was consistently the most potent NO-NSAID in all cell lines tested (except for the lung cancer cell line), sometimes in excess of 100-fold over the other three NO-NSAIDs. NO-NSAIDs inhibited cell proliferation, induced apoptosis, and altered cell cycle phase distribution (G2/M to G0/G1 block). All altered cellular morphology, whereas NO-aspirin induced nuclear disintegration ("atypical" cells) established by electron microscopy. NO-aspirin showed similar effects on two pancreatic cancer cell lines, BxPC-3 (expresses COX) and MIA PaCa-2 (no COX expression), suggesting a COX-independent effect. NO-NSAIDs showed a tissue-type-independent effect. Their pleiotropic effects involve cell renewal, cell death, and cell cycle phase transitions. These results raise the possibility that NO-NSAIDs possess chemopreventive and/or chemotherapeutic activity against a wide variety of human cancers. 

PMID: 12438552
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Leukemia. 2001 Dec;15(12):1852-9.

Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes.

Adams DJ, Levesque MC, Weinberg JB, Smith KL, Flowers JL, Moore J, Colvin OM, Silber R.

Department of Medicine, Duke University Medical Center, Durham, NC 27710

Fludarabine is active but not curative in the treatment of chronic lymphocytic leukemia (B-CLL). Nitric oxide (NO) supplied from exogenous, NO-donating pro-drugs can also induce apoptosis and death of acute leukemia cells. This study investigated combinations of fludarabine with NO-donating pro-drugs for their cytotoxicity against freshly isolated B-CLL lymphocytes following a 72 h exposure in vitro. The median IC(50)for fludarabine was 2.2 microM (n = 85). The nitric oxide donors DETA-NO, PAPA-NO, and MAHMA-NO were also cytotoxic, and their effects were inversely related to rates of NO release. Neither DETA-NO depleted of NO nor DETA itself was effective, indicating that NO was required for cytotoxicity. Drug interactions were evaluated by a modified combination index method. Synergy was observed in combinations of fludarabine or nelarabine (506U78) with DETA-NO in 52% and 88% of samples, respectively. Interestingly, the combination of fludarabine and DETA-NO was more cytotoxic in B-CLL cells less sensitive to fludarabine. DETA-NO did not enhance the activity of other DNA anti-metabolites, topoisomerase I and II inhibitors, or alkylating agents. Finally, the anti-leukemic activity of fludarabine alone or in combination with DETA-NO was found to correlate with inhibition of cellular RNA synthesis. These results indicate that NO donors could enhance fludarabine therapy for B-CLL.

PMID: 11753605
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Am J Physiol. 1999 Jun;276(6 Pt 1):G1313-6.

Nitric Oxide. V. therapeutic potential of nitric oxide donors and inhibitors. 

Muscara MN, Wallace JL. 

Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada T2N 4N1. 

Nitric oxide is a crucial mediator of gastrointestinal mucosal defense, but, paradoxically, it also contributes to mucosal injury in several situations. Inhibitors of nitric oxide synthesis and compounds that release nitric oxide have been useful pharmacological tools for evaluating the role of nitric oxide in gastrointestinal physiology and pathophysiology. Newer inhibitors with selectivity for one of the isoforms of nitric oxide synthase are even more powerful tools and may have utility as therapeutic agents. Also, agents that can scavenge nitric oxide or peroxynitrite are promising as drugs to prevent nitric oxide-associated tissue injury. Compounds that release nitric oxide in small amounts over a prolonged period of time may also be very useful for prevention of gastrointestinal injury associated with shock and with the use of drugs that have ulcerogenic effects. Indeed, the coupling of a nitric oxide-releasing moiety to nonsteroidal anti-inflammatory drugs has proven to be a valid means of substantially reducing the gastrointestinal toxicity of these drugs without decreasing their efficacy. 

PMID: 10362633
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The Science of NO-NSAIDs

I have come across two excellent articles that discuss the science of NO-NSAIDs. 

Much of the focus in clinical research with NO-NSAIDs is in the area of colon cancer and Alzheimer's disease. I suppose that makes sense, since there has been a wealth of documented evidence suggesting that the garden variety NSAIDs is effective in both of these areas and there now seems to be reason to hope that NO-NSAIDs will be even more effective. The table below is abstracted from one of the articles. It compares standard aspirin, ibuprofen and sulindac with their NO-counterparts. The test measures IC50, the concentration required to kill exactly 50% of the colon cancer cells, in a given amount of time. For example, after incubating for 24 hours, even at a maximum concentration of 5000 units, Aspirin was not able to kill 50% of the cells. Its counterpart, NO-aspirin, was able to do it at a miniscule concentration of just 1. (The difference between 24 hours, 48 hours and 72 hours for NO-aspirin is due to the error inherent in the measurement). I have to admit, these numbers knocked my socks off!! The rest of the article is equally interesting.

The IC50 of NO-NSAIDs in HT-29 cells (mM)
From Williams, et al., Cancer Research
Compound 24 h 48 h 72 h
Aspirin >5,000 2,540 2,540
NO-aspirin 1 2 2
Ibuprofen >1,000 >1,000 >1,000
NO-ibuprofen 42 48 44
Sulindac 750 682 240
NO-sulindac 150 33 12

Besides colon cancer and Alzheimer's disease, another logical area for potential use of NO-NSAIDs is in the area of heart disease. Like their standard counterparts, NO-NSAIDs are also good at preventing clumping of platelets, and therefore good at preventing blood clot formation, strokes etc. The NO-NSAIDs may be more potent, may need to be administered at much lower concentrations to get the same bang for the buck, and they are certainly less prone to creating gastric problems with long term use. For that reason they may be the preferred route. I am pointing this out because many CLL patients also suffer from low platelets and have to be aware of the dangers of using blood thinners of any kind, which would expose them to the risk of internal bleeding.

Some of you who are patients of Dr. Keating may have heard him talk about R-Flurbiprofen, the optically pure isomer of the common NSAID Flurbiprofen that Myriad Pharmaceutical is testing, as a way of inhibiting cancer cell growth. Anyone wants to take on the job of convincing him and the rest of the CRC experts to try NO-aspirin instead? I have already suggested it to him and Drs. Wierda and Kipps. But it helps to have more than one voice deliver the message. 

The paper gives the chemical structure of NO-aspirin. Pretty simple compound, any half-way decent organic chemist would be able to cook it up with standard lab ware in a couple of days, if he/she is not worried about patent infringement, FDA and all that stuff. Hard to believe, here are a series of compounds that are so simple, easy to make, expected to be  non-toxic, and they maybe the answer to keeping early stage CLL patients from proliferating to higher stages, keeping first remissions going on for much longer. Or responding much better to Fludarabine therapy. These compounds have the potential to be the "maintenance" drugs that will keep our people alive till something better comes along, that can actually cure CLL. And here is the heartbreaker: chances are none of these compounds will be in clinical trials for CLL any time in the near future. 

Abstracts:

Cancer Research

Nitric Oxide-releasing Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Alter the Kinetics of Human Colon Cancer Cell Lines More Effectively than Traditional NSAIDs

Implications for Colon Cancer Chemoprevention

Jennie L. Williams, Simona Borgo, Izhar Hasan, Eddy Castillo, Frank Traganos and Basil Rigas

American Health Foundation, Valhalla, New York 06595 [J. L. W., B. R.]; Division of Gastroenterology [J. L. W., I. H., E. C., B. R.] and Brader Cancer Canter [F. T.], New York Medical College, Valhalla, New York 06595; and Strang Cancer Prevention Center [S. B.] and Rockefeller University [B. R.], New York, NY

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs), consisting of a known nonsteroidal anti-inflammatory drug (NSAID) and a nitric oxide (NO)-releasing group, are reported safer than NSAIDs. To assess their potential in colon cancer chemoprevention, we studied in vitro the effect of NO-aspirin, NO-sulindac, and NO-ibuprofen on colonocyte kinetics. These three NO-NSAIDs reduced the growth of cultured HT-29 colon adenocarcinoma cells much more effectively than the corresponding NSAIDs; e.g., at 24 h, their IC50 values were as follows: (a) aspirin, >5000 µM; (b) NO-aspirin, 1 µM; (c) sulindac, 750 µM; (d) NO-sulindac, 150 µM; (e) ibuprofen, >1000 µM; and (f) NO-ibuprofen, 42 µM. This effect was due to inhibition of proliferation and induction of apoptosis and perhaps to the induction of novel cell changes, characterized by extensive DNA degradation. NO-NSAIDs also blocked the G0-G1 to S cell cycle transition. Their superior effectiveness compared with traditional NSAIDs, combined with their reported safety, makes them promising candidates for chemopreventive agents against colon cancer.
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Molecular Interventions

Chemoprevention Goes Gourmet: Different Flavors of NO-Aspirin

Ajay Goel1, Christoph Gasche2,3 and C. Richard Boland1

1 Division of Gastroenterology, Department of Medicine, Baylor University Medical Center, Dallas, Texas,
2 Medical University of Vienna, Department of Medicine,
3 Division of Gastroenterology and Hepatology, Vienna, Austria

SUMMARY: Among the salutary effects of aspirin (acetylsalicylic acid, ASA) are its ability to keep platelets from aggregating and blood from clotting too readily, to reduce fever, and to ameliorate inflammation. Aspirin also is beneficial in preventing colorectal cancer; however, aspirin is not without its side effects, which include gastrointestinal irritation and ulceration. Additionally, if a patient has pre-existing conditions that are exacerbated by aspirin, does a daily dose of aspirin make sense, when admittedly, the reduction of the incidence of colorectal cancer is less than 50% in those who take aspirin daily? New research on nitric oxide-modified aspirin (NO-ASA) indicates that the gastrointestinal side effects might be suppressed while keeping or enhancing the ability of the modified aspirin to prevent colorectal cancer and inhibit the proliferation of cancer cells in vitro.
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