Liver cancer drug

The developer of tamoxifen - a drug widely used to treat women with breast cancer - has just published data on the synthetic hormone's ability to cause liver cancer in rats. The incidence of these cancers was higher than expected at all doses used during the two-year study

Moreover, says John Topham, a toxicologist involved in the study the lowest dose studied produced i n the rats' blood a range of tamoxifen concentrations that overlapped those measured in women now taking the drug.

Word of this study began circulating in the medical literature as early as 1986, notes Joachim G. Liehr, a chemist at the University of Texas Medical Branch in Galveston. However, he notes, the Sept. 1 CANCER RESEARCH paper by Peter Greaves, Topham, and co-workers at ZENECA Pharmaceuticals in Alderley Park, England, represents the first formal publication of the study and its findings.

Like many other toxicologists studying tamoxifen, Liehr has been anxiously awaiting access to these data - especially since new studies by him and others over the past 18 months have begun turning up additional signs that the drug might pose a cancer risk, especially to the liver (SN: 4/25/92, p.266).

Further fueling interest in these data, the National Cancer Institute (NCI) in Bethesda, Md., launched an experimental trial last year to treat with tamoxifen several thousand healthy women at high risk of developing breast cancer (SN: 5/9/92, p.309). The new toxicity data have spawned considerable controversy over whether the federal government's cancer-prevention trial might actually jeopardize some women's overall health (SN: 11/28/92, p.378).

The ZENECA study found that, compared to rats given no drug, the group receiving just 5 milligrams of tamoxifen per kilogram of body weight daily developed 20 to 35 times more liver tumors - many of them highly invasive. They observed even higher rates of liver cancer among animals in the two highest-dose groups. Indeed, compared to untreated rats, animals in these high-dose groups had significantly elevated death rates.

Though liver cancers also killed some rats in the group receiving the lowest tamoxifen dose, "overall survival in this group was better than [that of untreated animals]," the researchers note, largely because of reductions in kidney disease and pituitary cancers. (They attribute these reductions to the reduced food consumption seen in animals treated with tamoxifen.)

Greaves' team concludes that "tamoxifen must be regarded as a hepatic carcinogen in rats." But the mechanism by which the drug fosters cancer remains unclear, they maintain. At issue, Topham says, is whether the cancer results from damage to DNA or from severe hormonal perturbations wrought by this compound, which can produce both estrogen and anti-estrogen effects.

Asked to comment on the Greaves liver-cancer report, tamoxifen expert Susan G. Nayfield of NCI said, "We are concerned about this." But she says the liver cancer is probably "species-specific," adding that NCI is "very carefully" monitoring tamoxifen patients, including those in the prevention trial, for liver problems.

Others remain less sanguine. Liehr and Gary M. Williams of the American Health Foundation in Valhalla, N.Y., have both observed tamoxifen's ability to generate adducts - a type of DNA alteration believed necessary to initiate many cancers. This suggests that tamoxifen's carcinogenicity traces to DNA damage, they say. And tamoxifen's ability to cause DNA changes in mice, rats, and hamsters "suggests that for adducts, there is no species specificity" says Williams.

During the 24 years tamoxifen has been used to treat breast cancer patients, only two human liver cancers have been reported. Concludes Williams, "Either it means it hasn't been looked for well enough or something is protecting humans [from this cancer]."