9 July 2003 12:00 GMT

by Stacy Fitzsimons

The search for novel anti-cancer compounds derived from marine organisms is picking up momentum, say researchers. Many such compounds are advancing steadily through clinical trials, while others follow close behind.

The National Cancer Institute (NCI) in the US is a major player in efforts to identify new cancer drugs from marine sponges. It spends about $750,000 each year collecting samples of marine plants and animals. The Institute collects up to 1000 new samples every year.

There are three major collectors worldwide, says David Newman of the Natural Products Branch of the NCI. These are the NCI (contracted to the Coral Reef Research Foundation), the Australian Institute of Marine Science (AIMS), and the Harbor Branch Oceanographic Institution in Florida. There is also a handful of smaller players who collect their own samples to analyze for drug potential. And there are perhaps two- or three-dozen labs working further down the track, says Newman.

The Scripps Oceanographic Institute in California is involved in all aspects of this work, from collecting sponges and isolating and studying potential anti-cancer compounds, to culturing the sponge species that produce specific compounds. Researchers based at the Institute have been working for several years to find cancer therapies from marine sponges and other organisms.

However, investigating marine organisms as possible sources of future cancer drugs is not without problems. Catherine Sincich at the Scripps Oceanographic Institute says that sometimes only a few sponges of a particular species can be found. This means a researcher can only take very small samples, which could yield an impossibly small amount of compound. Many labs looking for new anti-cancer agents also try to produce the molecule synthetically. This is done either chemically, or by isolating the gene that codes for the product of interest and expressing it in a bacterial culture system.

Some groups are also trying to culture the sponges they work with. This can be tricky, notes Sincich, with the problem of mimicking the deep-sea environment needed for the sponge to produce the same amounts of toxins as in the wild. Nevertheless, a few groups have succeeded, including researchers at AIMS, and the National Institute of Water and Atmospheric Research (NIWA) in New Zealand.

Researchers at Victoria University in New Zealand have found a chemical called Peloruside A that works in a similar way to the more expensive cancer drug Taxol. Both stabilize microtubules - the protein structures required by a cell to multiply and divide - and therefore cause the cancer cells they target to die. The researchers worked in collaboration with NIWA to culture the sponge that makes Peloruside A. "We are able to grow the sponge in aquaculture in the ocean from gram-sized explants to multi-kilogram sized individuals in less than one year," said researcher Peter Nothcote. "We do not have to rely on collecting from the wild to provide sizeable amounts of the cytotoxic metabolites."

Another problem with work on the metabolites extracted from sponge, according to Sincich, is that they are often less, or more, active in humans than in test tubes. So although a chemical may successfully fight off aggressive cancer cells in vitro, it might be extremely toxic in animal studies. This potency is usually due to the diluting effect of seawater, says Sincich. To be effective at chemical warfare in the wild, sponges must produce chemicals potent enough to affect their target despite dilution in the sea.

In addition, sponge-derived bioactive compounds sometimes show unwanted side effects. For example, a compound called Girolline, which had made it to Phase I clinical trials, had to be withdrawn after subjects showed signs of hypertension.

So research is focussing not only on artificial synthesis of possible anti-cancer compounds, but also on efforts to alter the chemical structure of those compounds in different ways. Sincich calls this combinatorial chemistry - combining the active part of the sponge chemical with another structure to reduce toxicity or increase selectivity.

So why are some of the chemicals produced by sponges able to fight off human cancer cells? The leading hypothesis is that sponges, being anchored in one position, make such agents to fight off attackers or to stop neighboring sponges competing for space and resources. But in the end, says Sincich, the biological role of these agents remains an enigma.

"No one really knows," she said. "It's been a question asked for decades by researchers all over the world. And scientists have really only been looking closely at their effects on mammalian cells since the 1970s."

Although it is a relatively small research field, the potential for identifying drugs in the ocean is vast, say researchers. This is especially true as diving and collecting techniques improve, and terrestrial environments such as rainforests are destroyed. Well over half the new cancer drugs approved since the 1980s are based on natural products or their derivatives.

No drug directly derived from a marine organism has yet been commercialized as an anti-tumor agent, says the NCI's Newman. But with some now in advanced clinical trials, this may be about to change. Newman estimates that there are at least 30 marine-derived products currently in preclinical or clinical trials for cancer. And many more are at earlier stages of development.