Enthusiasm for the use of retinoic acids as chemopreventive agents in lung cancer has waned in the last several years after patients in two large trials showed an unexpectedly disappointing response to such treatment. In fact, in both the Alpha-Tocopherol, -Carotene Cancer Prevention Study and the
-Carotene and Retinol Efficacy Trial (CARET), smokers who took
-carotene supplements had an increased risk of developing and dying of lung cancer.
However, when Jonathan Kurie, M.D., an oncologist at the University of Texas M. D. Anderson Cancer Center, Houston, and colleagues teased apart the data from these studies, they realized that former smokers did not show such increased risk, leaving open the question of whether such treatments may be beneficial to nonsmokers.
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RAR and Tumor Suppression
Retinoic acids and their corresponding nuclear receptors, the retinoic acid receptors, RAR,
, and
, and the retinoid X receptors, RXR
,
, and
, work together to regulate cell growth, differentiation, and death. Loss of one such receptor, RAR
, is associated with the development of precancerous lesions in the lung, and several lines of evidence indicate that RAR
has tumor suppression activity in the aerodigestive tract. Because of the importance of these activities, Kurie decided to look at RAR
expression in patients given retinoid supplements.
A total of 226 former smokers, all of whom had quit smoking at least 1 year prior to enrolling in the trial, were randomly assigned to one of three trial arms. Patients in the first arm received 100 mg per day of 9-cis retinoic acid (9cRA); patients in the second arm received 1 mg/kg of body weight per day of 13-cis retinoic acid (13cRA) plus 1200 IU -tocopherol, a synthetic vitamin E compound; patients in the third arm received a placebo.
The researchers took lung biopsies from six predetermined sites in each patient before treatment, after the 3-month treatment period, and 3 months after treatment cessation. Kuries team then analyzed the biopsies for histological abnormalities and for RAR expression. Of the 226 patients enrolled, the researchers have evaluated 177. Eleven patients dropped out because of treatment-related toxicities.
In healthy individuals with no history of smoking, 100% of biopsies should express RAR. However, in this population, which had an extended history of smoking, nearly 30% of the biopsies had no detectable RAR
expression. In the placebo-treated patients, the percentage of biopsies showing RAR
expression dropped from 75% to 69% over the course of the 6-month trial period. However, in the 9cRA-treated patients, the percentage of biopsies with RAR
expression increased from 69% to 76% over the same time period. The researchers found no substantial change in level of RAR
expression in patients taking 13cRA.
Kuries team also found a statistically significant reduction in the number of biopsies with metaplasia in the 9cRA-treated group relative to the control group. During the 6-month course of the study, the percentage of biopsies from patients in the placebo arm that had metaplasia dropped from 34.4% to 27.9%. In the patients treated with 9cRA, by contrast, the percentage of such biopsies decreased from 38.5% to 19.2% over the same time period.
The Biochemistry Behind the Data
The different effects of 9cRA versus 13cRA are not surprising given their distinct binding profiles. 9cRA is a "very potent" ligand of both RXR and RAR nuclear receptors, said Kurie. When the ligand binds to the receptors, the complex activates numerous genes, including the RAR gene. The amount of RAR
available to bind to the ligand, therefore increases, thereby effectively engaging a positive feedback loop, the end result of which is a decrease in cell proliferation.
13cRA, on the other hand, cannot bind the nuclear receptors directly but must first be converted into either 9cRA or all-trans retinoic acid (ATRA); ATRA binds only to RARs, not to RXRs. This intermediate step and the narrow receptor targets for ATRA may contribute to 13cRAs relative ineffectiveness as compared to 9cRA.
Despite their lack of current fashion, the fact that retinoids may have a protective effect is not surprising, said Xiang-Dong Wang, M.D., Ph.D., a scientist in the Nutrition and Cancer Biology Laboratory at Tufts University in Boston. Wang was the lead author on a study looking at the effects of tobacco smoke and supplementation with -carotene, a precursor to vitamin A, on RAR signaling and precancerous lesions in ferrets (
J Natl Cancer Inst 1999;91:60-6
In that study, the researchers found that giving animals high doses of -carotene (equivalent to an intake of 30 mg of
-carotene per day in humans, as administered in the CARET study) decreased the amount of retinoic acid in the lung and increased the rate of cell proliferation and the number of metaplasic lesions. Although this negative effect was exaggerated in animals exposed to tobacco smoke, the researchers saw deleterious effects in nonsmoking animals as well. In contrast, the researchers found that treating smoke-exposed ferrets with low doses of
-carotene (equivalent to an intake of 6 mg per day, comparable to doses in epidemiologic studies of humans) partially attenuated the smoke-induced drop in RAR
expression and retinoic acid levels in lung tissue and was protective against smoking induced squamous metaplasia.
Based on in vitro experiments, Wangs group found that the high doses of -carotene were being broken down into oxidative metabolites, particularly in the lungs of ferrets exposed to smoke. These oxidative metabolites induced cytochrome P450 enzymes, which then interfered with retinoic acid metabolism, down-regulating the RAR signaling pathwaysincluding RAR
expressionand enhancing cell proliferation.
But something is clearly different between Wangs ferret study and Kuries human one, something beyond the different organisms under study. Although the two organisms metabolize vitamin A-like compounds such as -carotene and 9cRA in the same manner, the two compounds are clearly not equivalent. Given the positive effects seen by Kurie, it seems unlikely that even high doses of 9cRA break down into damaging metabolites the way high doses of
-carotene do.
Wang says he is very excited about Kuries new work and now thinks that if Wangs laboratory had used 9-cis--carotene, which his laboratory has shown to be the precursor of 9cRA, they might have seen results similar to Kuries. However, he still cautions that until the metabolites are better understood, high doses could still cause unpredicted problems.
But even with the cautionary note, Wang said, "this study indicates that retinoids still play a role in chemo-prevention of lung cancer."
For his part, Kurie admits that all of this is still at the very early stages and may still not pan out. But he contends that, especially when dealing with a pleiotropic system like the retinoic acid signaling pathway, it is important to limit the patients under study. "We are learning more and more that these pathways are pleiotropic and have multiple effectors and depending on the cell type that you are studying or the in vivo context, you can have very different biologic effects," he said.
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