A lung cancer treatment that inhibits nicotine receptors was shown to double survival time in mice, according to Italian researchers.

The results of the early phase animal model study were reported in the June 15 issue of the American Journal of Respiratory and Critical Care Medicine.

Changes in genes encoding nicotine receptors are strongly associated not only with the tendency to smoke, but with susceptibility to lung cancer. Nicotine exposure also heightens the expression of the nicotine receptors, which leads to increased cell proliferation and inhibition of apoptosis, further setting the stage for cancer.

Patrizia Russo, Ph.D. and Laura Paleari, Ph.D. of the Lung Cancer Unit of the National Cancer Research Institute in Genoa, Italy and colleagues from San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care (IRCCS), Catholic University, Campus Biomedico University in Rome, Mario Negri Institute in Milan and CEA Gyf sur Yvette in France showed in past research that an antagonist of nicotine acetylcholine receptors (nAChRs), may serve as an anticancer agent. The antagonist, called d-tubocurarine/ -Cobratoxin ( -CbT), specifically targeted the 7 subunit of nAChRs, the area primarily associated with increased cell proliferation.

In this study, the authors took the research a step further and showed that -CbT could inhibit non-small cell lung carcinoma (NSCLC) growth and prolong life in non-obese/severe combined immunodeficient (NOD/SCID) mice that had human NSCLC grafted to their lungs. This study attempted to mimic human cancer conditions more closely by delaying treatment until the tumors were well-established. In addition to control mice that were untreated, the researchers randomized one third of the mice to receive standard chemotherapy.

They found that NOD/SCID mice treated with the standard chemotherapy agent, cisplatin, had a 16 percent longer median survival time than untreated mice (p= 0.05). Mice treated with -CbT, however, had an increased median survival time of 1.7-fold over the cisplatin-treated mice and 2.1-fold over the no-treatment controls (p=0.0005).

“The results of this study show that -CbT, a powerful, high-affinity -7-nAChR inhibitor, induces antitumor activity against NSCLC by triggering apoptosis,” wrote Dr. Russo. “The prolonged survival of -CbT-treated animals in our mouse model of NSCLC is most likely the result of several mechanisms, including various antiproliferative and antiangiogenic effects.”

The research also found that unaffected (i.e., noncancerous) cells showed no inhibition of proliferation when treated with -CbT, suggesting that the treatment would have limited if any toxic effects. Dr. Russo and colleagues postulated that this finding may be due to the reduced number of receptor binding sites on normal cells as opposed to cancerous cells. Conversely, they reported that cancer cells with the greatest number of receptor binding sites seemed to respond with the greatest sensitivity to the treatment.

“The goal of this research line is to explore the widest range of possibilities of intervention on the 7-nAChRs. We hope to move further on towards the clinical setting experimentation phase for the assessment of potentially new treatment strategies for NSCLC,” said Dr. Russo.

An editorial in the same issue of the journal asked if nicotine may be to lung cancer what estrogen is to breast cancer. Eliot R. Spindel, M.D., Ph.D., of Oregon Health & Science University, stated that estrogen can stimulate the development of breast cancer and estrogen-receptor antagonists, such as tamoxifen, provide therapeutic benefit. In support of a carcinogenic role for estrogen, the incidence of breast cancer appears to be decreasing as estrogen hormone replacement therapy is being used less often. Likewise, nicotine may promote lung cancer yet nicotine receptor antagonists may offer treatment options for patients with lung cancer.

John Heffner, M.D., past president of the ATS stated that “this research clearly has profound clinical implications regarding the role of nicotine in stimulating lung cancer and nicotine receptor antagonists in treating the disease. The highly addictive nature of nicotine, however, complicates patients’ ability to quit smoking and avoid ongoing nicotine exposure.”

“This [addictive nature of nicotine] underscores the importance of potential FDA regulation of nicotine in tobacco products to limit exposure to this drug that promotes tumor growth,” wrote Dr. Spindel.

Source
American Thoracic Society

• Explain to interested patients that this study did not identify the specific hospital factors that contributed to worse survival among black patients diagnosed with breast and colon cancer.

The nature of the hospitals that treat them might help explain why blacks fare worse than whites after a cancer diagnosis, researchers found.

After adjusting for patient and other factors, the effects of individual hospitals accounted for 36% of the excess mortality from breast cancer and 53.8% of the excess mortality from colon cancer among black patients, according to Tara Breslin, MD, of the University of Michigan in Ann Arbor, and colleagues.

Further studies will be needed to identify the specific system factors contributing to the disparate outcomes, they wrote in the Aug. 20 issue of the Journal of Clinical Oncology.

Breslin and her colleagues used data from the Surveillance Epidemiology and End Results-Medicare linked database to identify patients who underwent surgery after receiving a diagnosis of breast or colon cancer at 436 hospitals.

They included 25,571 patients with breast cancer (of whom 9.7% were black) and 22,168 patients with colon cancer (11.8% were black).

As expected, five-year survival rates were significantly lower among blacks — 62.1% versus 70.4% among whites for breast cancer and 41.3% versus 45.4% for colon cancer (P<0.001 for both).

The disparity remained after adjusting for age, cancer stage, and socioeconomic status.

The analysis also disclosed that hospitals with predominantly black patient populations had significantly worse five-year survival rates for both white and black patients diagnosed with breast (HR 1.32, 95% CI 1.20 to 1.45) and colon cancer (HR 1.27, 95% CI 1.18 to 1.37) than hospitals in which less than 10% of the patients were black.

“Our study is not the first to demonstrate the importance of system factors in explaining racial disparities in outcomes with specific conditions or procedures,” the researchers said.

They cited other studies showing that blacks had lower referral rates to high-volume centers, less access to high-quality surgeons, greater chances of experiencing treatment delays, and worse chances of receiving adjuvant therapy.

Although Breslin and her colleagues could not identify the specific hospital factors associated with worse survival, they said it might have to do with reduced access to high-quality staff and technology, or differences in how resources are allocated in hospitals treating more disadvantaged patients.

The study was limited, they said, by being limited to Medicare patients over 65.

“Racial disparities in late survival after cancer care may be even more pronounced in the large proportion of minority patients without insurance,” they said.

Additional limitations included the reliance on administrative data to identify comorbidities, which may have underestimated their contribution to overall mortality; the lack of patient-level measures of income, education, and other socioeconomic variables; limited statistical power for examining hospital subgroups, and the focus on blacks and whites only.