Get ready for chemotherapy with Viagra
Jacob Schor ND
October 21, 2006
Imagine you have cancer and tomorrow morning some nurse is going to pump you full of Adriamycin. What do you do to get ready?
Believe it or not, you should pop some Viagra. Viagra increases nitric oxide in your blood, which in turn will make the chemotherapy more effective at destroying cancer cells and, at the same time, protect your heart from chemo-caused toxicity.
Adriamycin, the brand name for the drug doxorubicin, is a common chemotherapy drug used to treat a range of different cancers. It comes with a price. The killing action of Adriamycin is nonspecific and injures healthy cells as well as cancer cells. It is worthwhile to look for ways to increase the benefits of using it while looking for ways to lessen the harm. Increasing benefit translates as increasing Adriamycin's cancer cell killing effect. Decreasing harm means decreasing the damage to organs like the heart, liver and kidney.
A 2004 study showed you could increase the effect of Adriamycin by adding nitric oxide to the mix. Breast cancer cells exposed to nitric oxide (NO) 30 minutes before treatment were much more sensitive to Adriamycin. Adriamycin treatment alone killed 60% of the cancer cells, but pre-treating the cells with NO and then treating with Adriamycin killed 95% of the cancer cells in the experiment. [i]
Simultaneous treatment with both NO and Adriamycin produced only a slight increase in cancer kill over treatment with Adriamycin alone. Giving NO after Adriamycin produced no change at all.
In an a variation of this experiment, 24 hour pretreatment of the cancer cells with a chemical that depletes glutathione, further increased the effectiveness of the NO and Adriamycin treatment. This combination killed 100% of the cancer cells in the experiment.
The obvious concern with using NO along with Adriamycin is whether this regime will increase the drug's toxic effect on healthy tissue. In this same study, the researchers ran healthy rat heart cells through the same protocols of NO pretreatment followed by Adriamycin. NO exposure did not increase the damage caused by Adriamycin on the healthy cells.
These results suggest that patients undergoing treatment with Adriamycin should look at two approaches to increasing the benefit. First, increase NO production prior to treatment. Second, lower glutathione levels during treatment.
I've written elsewhere about glutathione depletion as a cancer treatment strategy, so in this article, let's focus on nitric oxide, which is a hot research topic these days. NO produces a number of different effects, the one of which is dilation of blood vessels. This effect lends NO to be used for a variety of applications ranginig from treating heart angina by increasing blood flow to the heart, to treating erectile dysfunction (ED) by increasing blood flow to you know where.
So how do you increase nitric oxide? The method most people are familiar with is Viagra. Viagra belongs to a class of drugs known as phophodiesterase-5- inhibitors (PDE- inhibitors). These drugs slow down the action of an enzyme that breaks down nitric oxide thus increasing its apparent effect.
When it comes to Adriamycin, Viagra appears to do what we want. A 2005 study reports that Viagra pre-dosing prior to Adriamycin treatment decreases cardiotoxicity while at the same time increasing the damage caused by Adriamycin to the cancer cells. [ii] At least it did so in mice. Other drugs PDE-inhibitors, cousins to Viagra, which last longer, may be more effective than Viagra. For example, while Viagra has a half-life of just 4 hours, Tadalafil's half life is 17.5 hours; it lasts a day and a half.
Viagra is not the only way to increase NO production in the body. Taking the amino acid arginine achieves, over time, nearly the same result as Viagra. The body converts arginine into nitric oxide; if there is more arginine around, the body makes more NO. Several studies have tested arginine as a treatment for erectile dysfunction with varied results. A 17-day trial using 1500 mg a day of arginine produced disappointing results. [iii] Another trial using 5,000 mg per day for 14 day produced positive responses in about one third of the participants. [iv] Great results were reported when arginine was combined with pycnogenol in a longer, high dose trial. Pycnogenol increases production of NO through the enzyme nitric oxide synthase. After three months of treatment using 120 mg of pycnogenol and just under 2 grams of arginine per day, 92% of the participants reported normal function. [v] The shorter earlier studies may just not have lasted long enough to notice and effect or it may be that pycnogenol boosted effect.
Another amino acid, citrulline, may also be useful. When the enzyme nitric oxide synthase (NOS) converts arginine into nitric oxide (NO) it produces some leftover citrulline. The same cells that make NO, convert the citrulline back into arginine. [vi] For some reason (that I don't understand yet), combining arginine with citrulline in a four to one ratio is felt to be more effective at generating NO than using arginine alone.
This entire idea of using NO as a pretreatment to chemotherapy is new, and admittedly still weakly researched. The studies mentioned involved test tubes and mice, not people.
As much fun as focusing on NO before chemo may sound, there are other ways to protect patients from Adriamycin damage that probably should be considered first. Clinical experience supports the use of coenzyme Q-10 and l-carnitine during Adriamycin therapy.
The take home point of this discussion is not whether patients should be force-fed Viagra prior to chemotherapy. Instead, the point is that there are ways to increase chemotherapy benefit while lessening chemotherapy damage. The medical oncology community rarely considers these sorts of options, often to the detriment of patients.
This Viagra and nitric oxide approach although real and serious is still entertaining to joke about; it is one of numerous possible adjunctive treatments that should be considered whenever a patient contemplates chemotherapy. Yet for the cancer patient faced with the decision of whether or not to undergo chemotherapy, these options bring hope.
Chemotherapy has its pros and its cons. Increasing tumor kill effectiveness bolsters the argument in favor of using chemotherapy. At the same time, reducing chemo's toxic side effects weakens the arguments against therapy. This knowledge can change the way one looks at the risk/benefit balance enough to change one's decision regarding treatment. Anything we can do to shift the balance in favor of a positive outcome during cancer therapy, we should do.
Endogenous production and exogenous exposure to nitric oxide augment doxorubicin cytotoxicity for breast cancer cells but not cardiac myoblasts.
Evig CB ,
Kelley EE ,
Weydert CJ ,
Chu Y ,
Buettner GR ,
Burns CP .
Department of Medicine, The University of Iowa Carver College of Medicine and The University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA.
We studied the effect of nitric oxide (*NO) on the anticancer activity of doxorubicin. When MCF-7 human breast cancer cells were exposed to an aqueous solution of *NO delivered as a bolus 30 min prior to doxorubicin, the cytotoxic effect as measured in a clonogenic assay was increased (doxorubicin alone, 40% survival, doxorubicin plus *NO, 5% survival). The *NO donor diethylamine nitric oxide, but not inactivated donor, also yielded an increase in doxorubicin cytotoxicity. The sequence was important since the simultaneous application of *NO with doxorubicin yielded only a small augmentation of effect, and the exposure of the cells to doxorubicin prior to the *NO obliterated the augmentation. Prior depletion of glutathione by incubation of the cells for 24h with D,L-buthionine-S,R-sulfoximine (BSO) further increased the cytotoxicity so that BSO plus *NO plus doxorubicin killed all of the clones. MCF-7 cells transduced with inducible nitric oxide synthase gene (iNOS) through an adenoviral vector overexpressed iNOS and produced increased amounts of nitrite, an indicator of increased *NO production. These iNOS transduced cells were more susceptible to doxorubicin than vector control or wild-type cells. Cell cycle progression of iNOS transduced cells was not different from controls. Likewise, iNOS transduction resulted in no change in cellular glutathione levels. For comparison, we examined the effect of iNOS transduction on the sensitivity of MCF-7 to edelfosine, a membrane-localizing anticancer drug without direct DNA interaction. Insertion of the iNOS had no effect on killing of the MCF-7 cells by this ether lipid class drug. We also tested the effect of iNOS transduction on doxorubicin sensitivity of H9c2 rat heart-derived myoblasts. We found no augmentation of cytotoxicity by *NO, and this observation offers potential therapeutic tumor selectivity by using *NO with doxorubicin. Therefore, we conclude that *NO produced intracellularly by iNOS overexpression or delivered as a bolus sensitizes human breast cancer cells in culture to doxorubicin, but not to a cardiac cell line or to edelfosine. This augmentation is not due to a modulation of cell cycle distribution or measurable cellular glutathione resulting from the transduction.
PMID: 15158691 [PubMed - indexed for MEDLINE]
[ii] Circulation. 2005 Apr 5;111(13):1601-10. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity.
* Fisher PW,
* Salloum F,
* Das A,
* Hyder H,
* Kukreja RC.
Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University Medical Center , Richmond 23298 , USA .
BACKGROUND: Sildenafil, a phosphodiesterase-5 inhibitor, induces cardioprotection against ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels. It is unclear whether sildenafil would provide similar protection from doxorubicin-induced cardiotoxicity. METHODS AND RESULTS: Male ICR mice were randomized to 1 of 4 treatments: saline, sildenafil, doxorubicin (5 mg/kg IP), and sildenafil (0.7 mg/kg IP) plus doxorubicin (n=6 per group). Apoptosis was assessed with the use of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and in situ oligo ligation methods. Desmin distribution was determined via immunofluorescence. Bcl-2 expression was analyzed by Western blot. Left ventricular function was assessed by measuring developed pressure and rate pressure product in Langendorff mode. ECG changes indicative of doxorubicin cardiotoxicity were also measured. For in vitro studies, adult ventricular cardiomyocytes were exposed to doxorubicin (1 micromol/L), sildenafil (1 micromol/L) with or without N(G)-nitro-L-arginine methyl ester (L-NAME) (100 micromol/L), or 5-hydroxydecanoate (100 micromol/L) 1 hour before doxorubicin and incubated for 18 hours. Doxorubicin-treated mice demonstrated increased apoptosis and desmin disruption, which was attenuated in the sildenafil+doxorubicin group. Bcl-2 was decreased in the doxorubicin group but was maintained at basal levels in the sildenafil+doxorubicin group. Left ventricular developed pressure and rate pressure product were significantly depressed in the doxorubicin group but were attenuated in the sildenafil+doxorubicin group. ST interval was significantly increased in the doxorubicin group over 8 weeks. In the sildenafil+doxorubicin group, ST interval remained unchanged from baseline. Doxorubicin caused a significant increase in apoptosis, caspase-3 activation, and disruption of mitochondrial membrane potential in vitro. In contrast, sildenafil significantly protected against doxorubicin cardiotoxicity; however, this protection was abolished by both L-NAME and 5-hydroxydecanoate. CONCLUSIONS: Prophylactic treatment with sildenafil prevented apoptosis and left ventricular dysfunction in a chronic model of doxorubicin-induced cardiomyopathy.
[iii] Urol Int. 1999;63(4):220-3.
Effectiveness of oral L-arginine in first-line treatment of erectile dysfunction in a controlled crossover study.
Klotz T, Mathers MJ, Braun M, Bloch W, Engelmann U.
Department of Urology, University of Cologne , Germany . email@example.com
BACKGROUND AND AIMS: Relaxation of cavernous smooth muscle is a parasympathetic and non-adrenergic, non-cholinergic mediated process which requires nitric oxide (NO). NO is synthesized from L-arginine by NO synthase (NOS). Some studies report good clinical results under oral L-arginine medication in the treatment of erectile dysfunction. We examined the effectiveness and safety of L-arginine in the treatment of mixed-type impotence. METHODS: 32 patients (mean age 51.6 years) with mixed-type impotence diagnosed according to the results of sexual history and urological examination were enrolled in a randomized, placebo-controlled, crossover comparison of an oral placebo with 3 x 500 mg L-arginine/day. A validated questionnaire (KEED) was used to define the grade of impotence with a score. The treatment consisted of two 17-day courses (50 tablets). After a 7-day washout period the patients who initially received the placebo for 17 days were switched to L-arginine and vice versa. We assessed the efficacy with the validated questionnaire at the end of each drug period. RESULTS: 30 patients (94%) completed the whole treatment schedule. Five (17%) patients reported a significant improvement in erectile function at the end of the L-arginine phase and 6 (20%) patients after the placebo period. 17 (56%) patients showed little improvement with L-arginine and 13 (43%) with placebo. In 8 patients (27%) of the verum group there was either no change in the ED score or even a slight worsening. No statistical difference in the impotence scores were found. No drug-related adverse effects occurred with L-arginine treatment. CONCLUSION: Oral L-arginine 3 x 500 mg/day is not better than placebo as a first-line treatment for mixed-type impotence.
[iv] BJU Int. 1999 Feb;83(3):269-73
Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study.
Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H.
Department of Urology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
OBJECTIVES: To determine, in a prospective randomized, double-blind placebo-controlled study, the effect of 6 weeks of high-dose (5 g/day) orally administered nitric oxide (NO) donor L-arginine on men with organic erectile dysfunction (ED). PATIENTS AND METHODS: The study included 50 men with confirmed organic ED who were randomized after a 2-week placebo run-in period to receive L-arginine or placebo. A detailed medical and sexual history, O'Leary's questionnaire, a specially designed sexual function questionnaire and a sexual activity diary were obtained for each patient. All participants underwent a complete physical examination including an assessment of bulbocavernosus reflex and penile haemodynamics. Plasma and urine nitrite and nitrate (designated NOx), both stable metabolites of nitric oxide, were determined at the end of the placebo run-in period, and after 3 and 6 weeks. RESULTS: Nine of 29 (31%) patients taking L-arginine and two of 17 controls reported a significant subjective improvement in sexual function. All objective variables assessed remained unchanged. All nine patients treated with L-arginine and who had subjectively improved sexual performance had had an initially low urinary NOx, and this level had doubled at the end of the study. CONCLUSIONS: Oral administration of L-arginine in high doses seems to cause significant subjective improvement in sexual function in men with organic ED only if they have decreased NOx excretion or production. The haemodynamics of the corpus cavernosum were not affected by oral L-arginine at the dosage used.
[v] J Sex Marital Ther. 2003 May-Jun;29(3):207-13.
Treatment of erectile dysfunction with pycnogenol and L-arginine.
Stanislavov R, Nikolova V.
Seminological Laboratory SBALAG, Maichin Dom, Sofia , Bulgaria . firstname.lastname@example.org
Penile erection requires the relaxation of the cavernous smooth muscle, which is triggered by nitric oxide (NO). We investigated the possibility of overcoming erectile dysfunction (ED) by increasing the amounts of endogenous NO. For this purpose, we orally administered Pycnogenol, because it is known to increase production of NO by nitric oxide syntase together with L-arginine as substrate for this enzyme. The study included 40 men, aged 25-45 years, without confirmed organic erectile dysfunction. Throughout the 3-month trial period, patients received 3 ampoules Sargenor a day, a drinkable solution of the dipeptide arginyl aspartate (equivalent to 1.7 g L-arginine per day). During the second month, patients were additionally supplemented with 40 mg Pycnogenol two times per day; during the third month, the daily dosage was increased to three 40-mg Pycnogenol tablets. We obtained a sexual function questionnaire and a sexual activity diary from each patient. After 1 month of treatment with L-arginine, a statistically nonsignificant number of 2 patients (5%) experienced a normal erection. Treatment with a combination of L-arginine and Pycnogenol for the following month increased the number of men with restored sexual ability to 80%. Finally, after the third month of treatment, 92.5% of the men experienced a normal erection. We conclude that oral administration of L-arginine in combination with Pycnogenol causes a significant improvement in sexual function in men with ED without any side effects.
Role of the l-citrulline/l-arginine cycle in iNANC nerve-mediated nitric oxide production and airway smooth muscle relaxation in allergic asthma.
Maarsingh H ,
Leusink J ,
Zaagsma J ,
Meurs H .
Department of Molecular Pharmacology, University Centre for Pharmacy, A. Deusinglaan 1, 9713 AV Groningen , The Netherlands .
Nitric oxide synthase (NOS) converts l-arginine into nitric oxide (NO) and l-citrulline. In NO-producing cells, l-citrulline can be recycled to l-arginine in a two-step reaction involving argininosuccinate synthase (ASS) and -lyase (ASL). In guinea pig trachea, l-arginine is a limiting factor in neuronal nNOS-mediated airway smooth muscle relaxation upon inhibitory nonadrenergic noncholinergic (iNANC) nerve stimulation. Moreover, in a guinea pig model of asthma iNANC nerve-induced NO production and airway smooth muscle relaxation are impaired after the allergen-induced early asthmatic reaction, due to limitation of l-arginine. Using guinea pig tracheal preparations, we now investigated whether (i) the l-citrulline/l-arginine cycle is active in airway iNANC nerves and (ii) the NO deficiency after the early asthmatic reaction involves impaired l-citrulline recycling. Electrical field stimulation-induced relaxation was measured in tracheal open-rings precontracted with histamine. l-citrulline as well as the ASL inhibitor succinate did not affect electrical field stimulation-induced relaxation under basal conditions. However, reduced relaxation induced by a submaximal concentration of the NOS inhibitor N(omega)-nitro-l-arginine was restored by l-citrulline, which was prevented by the additional presence of succinate or the ASS inhibitor alpha-methyl-d,l-aspartate. Remarkably, the impaired iNANC relaxation after the early asthmatic reaction was restored by l-citrulline. In conclusion, the l-citrulline/l-arginine cycle is operative in guinea pig iNANC nerves in the airways and may be effective under conditions of low l-arginine utilization by nNOS (caused by NOS inhibitors), and during reduced l-arginine availability after allergen challenge. Enzymatic dysfunction in the l-citrulline/l-arginine cycle appears not to be involved in the l-arginine limitation and reduced iNANC activity after the early asthmatic reaction.
PMID: 16919264 [PubMed - in process]