By Dean A. Haycock

Special To BioWorld Today

If there is a hierarchy in the pharmacopoeia, noscapine may be in for a promotion.

An alkaloid derived from opium, noscapine could eventually rise from cough medicine to anticancer drug on the strength of new research described in the Feb. 17, 1998, Proceedings of the National Academy of Sciences.

Used as a cough suppressant for decades in humans, noscapine constitutes between 1 and 10 percent of the total alkaloids in opium. Although the mechanism behind its antitussive effects is unknown, recent findings show the compound has an interesting array of pharmacological actions beyond its ability to suppress coughs.

It kills tumor cells by interfering with the cellular support architecture they depend on during cell division. As a result, it induces apoptosis, or programmed cell death, in many cell types. It also demonstrates antitumor activity against mouse solid lymphoid tumors and against human breast and bladder tumors grown in mice.

Human breast cancer tumors regressed by 80 percent following a three-week period of intraperitoneally administered noscapine. The drug also was reported to reduce human transitional cell carcinoma in mice by more than 60 percent.

Adding further to its apparent qualifications as an antitumor drug are noscapine's water-solubility and oral availability. It is non-addictive and has racked up a safe record after years of use by humans.

Harish Joshi, associate professor of cell biology at the Emory University School of Medicine, in Atlanta, and his co-authors describe these previously unrecognized, potentially therapeutic attributes of the antitussive drug in their paper, "Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells."

Noscapine Displays Antimitotic Capabilities

Chemically, noscapine shares superficial similarities with other, better known antimitotic agents, such as colchicine. Antimitotic agents stop cell division by interfering with the assembly of microtubules, cellular support elements composed of tubulin protein subunits. An important component of the cytoskeleton, microtubules are in constant flux.

One way cells employ microtubules is to separate chromosomes during mitosis, or cell division. This process requires the dynamic assembly and disassembly of microtubules in a structure called a mitotic spindle.

"Some small compounds that interact with tubulin or microtubules can alter the rate at which they assemble or shrink," Joshi said.

A few of these antimitotic agents are effective cancer fighters. The group that includes vinca alkaloids and colchicine inhibits the assembly of microtubules. The group that includes compounds such as the anticancer drug Taxol promotes microtubule assembly. Since cells don't respond well to agents that meddle with the buildup or breakdown of their interior architectural supports, the effects of these two groups of antimitotic agents are similar. When the finely regulated steps in mitosis are disrupted by either promoting microtubule assembly or stopping it, cells may respond by killing themselves.

The initiation of apoptosis is an excellent mechanism for stopping the uncontrolled growth of malignant cells long before a cancer can develop and spread.

Joshi and his colleagues showed noscapine also is an antimitotic agent. It binds to tubulin on a one-to-one basis and changes the shape of the building blocks enough to interfere with the assembly of microtubules. But it has some potentially important advantages over vinca alkaloids and Taxol, which is sold by Bristol-Myers Squibb Co., of New York.

Its water solubility means it would not be necessary to infuse the drug into patients. Also, unlike some other antimitotic agents, noscapine does not appear to affect microtubules in non-dividing types of cells such as neurons. Thus, it appears to lack the neurological side effects characteristic of antimitotic cancer drugs currently in use.

"Noscapine doesn't seem to do much to other cellular microtubules because it just interferes with the dynamics of microtubules. Dynamics is more important during major rearrangement, such as major cell division. It has potential advantages over these other compounds," Joshi said.

Since submission of the PNAS paper, Joshi and his team have shown that noscapine initiates apoptosis in many types of mammalian cells. "Because cells cannot form a perfectly functional spindle, they get arrested in the M [mitotic] phase-like state. That targets these cells to commit suicide, or start apoptosis," Joshi said. That work has been submitted for publication.

The Atlanta scientists now are aggressively pursuing opportunities presented by their discovery of noscapine's anticancer potential.

"I envision making a collaborative group that would include chemists, toxicologists, biologists like myself and clinicians such that we can have a multipurpose approach to this problem," Joshi said.

The ultimate goal would be to test a compound in the clinic.

"We have this compound [noscapine] as a lead compound now. That enables us to synthesize related compounds so we can select the most efficacious in treating cancer," Joshi said.

Two months ago, the group submitted a provisional patent application covering its discovery.

"We can either do a clinical trial ourselves or I am hoping that some company might like to follow it up," Joshi said. *