By David N. Leff

Cigarette smoking is big business. So is quitting.

In pharmacies and health food stores, alongside arrays of herbal and alternative remedies stand tall displays of smoking-cessation nicotine patches, nicotine chewing gum, nicotine inhalers and other devices designed to smooth the rocky road from tobacco addiction to recovery.

¿Tobacco smoke,¿ observed vascular biologist and clinician John Cooke, at Stanford University, ¿contains 4,000 constituents. Nicotine is the one of them that produces sensations of pleasure and alertness in its users¿ brains. It¿s addictive.¿

It¿s precisely nicotine¿s addictive properties that, paradoxically, spearhead the efforts of would-be quitters. While forsaking the tar and combustion products of cigarettes, they use the nicotinic cessation devices to taper off from their dependence.

But Cooke hints at ¿unintended consequences.¿ He is senior author of an article in the July 2001 issue of Nature Medicine, titled: ¿Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis.¿

¿Nicotine can be good or it can be bad,¿ he told BioWorld Today. ¿ It can be therapeutic or pathological. In this article we focused on the pathological aspects. We report that nicotine accelerates tumor growth, because it enhances the tumor¿s proliferation of new blood vessels ¿ angiogenesis. Atherosclerotic plaque,¿ he added, ¿as well as tumors, need small blood vessels to grow.

¿Actually,¿ Cooke pointed out, ¿the first good evidence of that neovascularization was provided by Judah Folkman, the pioneer of angiogenesis. About two years ago he showed that endostatin, an angiogenic inhibitor, can reduce the growth of the vessels into the plaque.¿

Nicotine Nailed In Cancer, Atherosclerosis

¿In our experiments, of course,¿ Cooke went on, ¿we were doing the reverse ¿ stimulating pathological angiogenesis with nicotine. We showed that it increased plaque vascularity and growth.

¿Plaque,¿ he explained, ¿is hardening of the arteries ¿ atherosclerosis. Plaque is a lot like a coral reef. Both are inanimate but are composed of living things. Plaque can be remodeled by lowering one¿s cholesterol. We found that nicotine speeded plaque growth by increasing the tiny blood vessels that grow into and feed it. A plaque looks a lot like an abscess. It consists mainly of lipid, cholesterol and dead cells.¿

Cooke related how he and his team serendipitously hit upon this unexpected role of nicotine.

¿We had the completely wrong idea,¿ he recalled, ¿that tobacco would impair angiogenesis. We based that hypothesis on the observations of others, that smoking damages endothelial vasodilator function. So we thought that tobacco would impair that ¿ and it probably does. But we used nicotine, not tobacco. And that was the wrong idea.¿

¿So I sent a medical student off to do this experiment,¿ Cooke recounted. ¿He came back four weeks later with the data, and he said, I¿m sorry, Dr. Cooke, the experiment didn¿t work.¿ So I asked, What happened? Did you have technical problems?¿ No no,¿ he answered, just that the data looked kind of funny.¿ I looked at it, and I said, This is great, amazing. It just changes our hypothesis. It¿s the nicotine that accelerates angiogenesis.¿

¿And as it turned out, nicotine is as potent as anything like fibroblast growth factor and vascular endothelial growth factor being currently used in antitumor clinical trials. It¿s as potent as those agents in inducing angiogenesis.¿

The co-authors carried out four mouse experiments to cinch nicotine¿s surprising role in angiogenesis:

¿Our first model of angiogenesis,¿ he recounted, ¿occurs in a setting of chronic inflammation. Say you have a foreign body in you, in the liver or someplace ¿ a big chunk of something that doesn¿t belong there. To get rid of that you need inflammatory cells to go in there, rip it apart and take it away. But those cells need blood vessels to deliver them there. Sometimes, if the foreign object is large enough, vessels will grow into it and deliver those white blood cells. It¿s a form of angiogenesis.

¿So what we did,¿ Cooke said, ¿was plant discs of plastic sponge under the skin in the backs of these mice. We impregnated the discs with our choice of growth factor, to enhance angiogenesis, or anti-growth factor to inhibit angiogenesis. In the first experiment, we put nicotine into the discs. We thought that would inhibit angiogenesis. Instead, it markedly accelerated vascular growth into the discs. Next, instead of inserting a disc under the skin, we put in tumor cells, and then gave the cells nicotine, which accelerated the growth of the tumor fivefold. It gave us a big tumor nodule after two or three weeks.

¿In the third experiment,¿ Cooke continued, ¿we fed the mice a high-cholesterol diet. They developed atherosclerotic plaques, accelerated by nicotine, which increased the density of vessels in the plaques.¿

Three Disease Models; One Limb Rescue

¿The first three experiments¿ Cooke observed, ¿were kind of pathological in angiogenesis, but then, in the fourth and last experiment ¿ on the flip side ¿ we showed that we could tie off a blood vessel to a limb and therapeutically accelerate the growth of new blood vessels with restored blood flow.¿

Cooke sees broader clinical applications for this new nicotine pathway.

¿In neurodegenerative diseases, such as Alzheimer¿s and Parkinson¿s,¿ he surmised, ¿nicotine or nicotine-like agents may be useful to increase alertness and cognitive function. Something that could stimulate nicotine receptors in the brain might be designed in such a way that it wouldn¿t stimulate blood vessels. Another possibility would be using nicotine capable of affecting formation of new blood vessels following heart attack or stroke.

¿But the warning from this study,¿ Cooke cautioned, ¿is that any such possible therapies should be fully explored, but with the concern in the back of the investigator¿s mind that systemic administration of nicotine patches and other smoking-cessation devices can have unintended consequences ¿ namely, tumor and plaque. Lately I¿ve been talking to people who¿ve been using nicotine patches for two years. Also, women taking it for weight loss, which is not what nicotine is indicated for. It¿s very sensible to use patches for a few weeks to get you off cigarettes. It¿s important to use them because tobacco smoke is directly injurious to tissues of the body.¿

Cooke and his team are not pursuing these therapeutic potentials, but the university has licensed the patent to his invention to Endovasc Ltd. Inc., of Montgomery, Texas, for development.

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