Chemotherapy drugs are a major weapon used daily by oncologists, but some cancer cells are resistant to them. Now researchers at the Technion-Israel Institute of Technology in Haifa have uncovered mechanisms used by cancer cells to resist these drugs. The discovery could have important ramifications by pointing the way to new approaches for fighting drug-resistant tumors. The findings of the Technion team, headed by biology Prof. Yehuda Assaraf, have been published in two articles in Cancer Research. In the first project, Assaraf and research student Assaf Shafran discovered that during chemotherapy, a genetic mutation occurs in a protein called ABCG2. This mutation gives the protein an ability to transport a wide variety of anticancer drugs from the anti-folate family outside the malignant cell. Anti-folates are used in treating various cancerous growths such as breast cancer, colon cancer, leukemia, and cancer of the membrane that envelops the lung. As a result, these malignant cells avoid the effects of the drugs and become extremely resistant to them, leading to a rapid spread of the disease. The researchers succeeded in delaying the mutation, making it possible for the drugs to do their intended work. "The mutation is an event in which a single amino acid changes in the structure of the ABCG2 protein, which then acts as a pump to transfer out the various anticancer drugs," explains Assaraf. "Acting as 'super-pumps,' the mutated ABCG2 proteins make cancer cells 6,000 times more resistant to various anticancer drugs." The researchers are already working on developing drugs to stop the ABCG2 mutation from occurring. In the second project, published in at the beginning of December, Assaraf and doctoral student Ilan Ifergan discovered another ABCG2 carrier resistance mechanism: Cancer cells create "wastebaskets" into which anti-cancer drugs are deposited. They discovered that healthy cells near breast cancers create balloon-like vesicles that serve as self-emptying wastebaskets into which the mutated ABCG2 proteins move the anti-cancer drugs. "The mutated ABCG2 protein is found in large quantities in the extra cellular membrane of these vesicles located among the neighboring cancer cells. It "cleans" the cancer cells of chemotherapy drugs such as mitoxantrone and collects them in these vesicles, which enlarge and inflate until the drug concentration is 1,000 times greater than in the surrounding cell culture," explains Assaraf. "This is a completely new resistance mechanism practiced by breast cancer cells to fight the lethal activities of anticancer drugs." Just as in their earlier study, the researchers were able to demonstrate that delaying the mutation left the anticancer drugs inside the malignant cells, making it possible to kill them effectively. PRE-BABY PUFF BRINGS SPECIAL DANGERS Women who smoke their first cigarettes before their first full-term pregnancy have a 20% higher risk of contracting breast cancer than women who started smoking after the birth of their first child or were never smokers. Mayo Clinic researchers, who conducted a retrospective study of the smoking habits of 42,000 post-menopausal American women, have reached such a conclusion. "Considering the young average age at smoking initiation, this study provides further justification for smoking prevention efforts aimed at young women," says Dr. Janet Olson, a Mayo Clinic researcher in Rochester, Minnesota and lead author of the Mayo Clinic Proceedings study. The risk estimates for women who smoked before their first pregnancy were 20% higher than those of nonsmokers, while women who started after their first pregnancy had rates of cancer similar to those who never smoked. The researchers did not find evidence that duration of smoking or number of cigarettes smoked affected the risk of breast cancer. Scientists have known for many years that women who are under 20 when they have their first baby are less likely to get breast cancer than those who are first-time mothers after 35. This is thought to be linked to the changes that take place in women's breasts during pregnancy. Breast cancer usually starts from cells that are most like the cells found in a woman before she has her first child. When she has her first baby, a woman's breasts change so she will be able to breastfeed. One theory is that the breast cells of women before they have their first baby are more likely to be damaged by things that can cause cancer. If a woman has her first baby sooner rather than later, then when she is exposed to things that cause cancer, she has fewer of the breast cells that are most likely to be damaged by that exposure. WHO TELLS STAFFERS: PUFF OFF The World Health Organization says it will no longer hire smokers under a tough new policy introduced to protect its credibility as the UN's health agency. The policy, announced to job seekers on its Web site, may have some applicants fuming. "WHO has a smoke-free environment and does not recruit smokers or other tobacco users," it states. Application forms ask candidates if they smoke and if they would continue to do so if they were employed by the WHO. A WHO spokesman said that anyone who answers "yes" to both questions will not be invited to an interview. "The agency believes its credibility in promoting the principle of a tobacco free environment is at stake," he said. "[We are] campaigning against tobacco and the tobacco industry," he said, with the WHO leading efforts to adopt the international anti-tobacco treaty. "For us, it's a question of principle." WHO lawyers have determined that it is "not discriminatory." The WHO's Framework Convention on Tobacco Control, which came into force this year and which has been ratified by about 100 countries (including Israel, where it has not yet been widely implemented), bans the promotion and advertising of tobacco products, as well as sales to minors. It also advocates public smoking restrictions and larger health warnings on cigarette packs, and promotes taxation as a way to cut consumption and fight smuggling. The new policy will not apply to existing WHO employees, but they are being encouraged to quit through individual counselling and prescriptions for nicotine replacement therapy such as patches and gum. But the new policy will apply if an employee leaves the agency and later returns to work; a growing number of WHO staff are recruited on short-term contracts. In addition, disciplinary action will be taken against a serving staff member who smokes on its premises. However, a leading Swiss anti-smoking campaigner, Jean Charles Rielle, said he felt "ill at ease" with the move, and opposed it as a matter of principle. "As a doctor, I cannot accept that a person suffering from a dependency, whatever it is, should be excluded if they are able to carry out the objectives set by the company," Rielle told the Swiss newspaper, Le Temps.