© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 1, 1,
January 5, 2000
© 2000 Oxford University Press
IN THIS ISSUE |
Molecular signals in a cancer cell's microenvironment may trigger survival-promoting mechanisms, thereby leading to resistance to chemotherapy. Taylor et al. (p. 18) examined three survival-promoting pathways, individually or in combination, to test their ability to prevent cell death in human B lymphoma cells treated with the drug etoposide. The authors found that the combination of all three survival signals reduced etoposide-induced apoptotic cell death by approximately fourfold, a difference that was statistically significant. Additional experiments by the researchers shed light on the molecular mechanism of the protective effect at the Bcl-2 protein family locus. Taylor et al. suggest that the interactions they observed may provide a model in other tumors for understanding drug resistance induced by the cell's environment.
In an accompanying editorial, Shoemaker (p. 4) places the findings of Taylor et al. in the context of the history of drug resistance research. He notes that genetic factors were the first to be described as contributing to drug resistance, but studies comparing resistance in monolayer and spheroid cultures of tumor cells and emerging studies of apoptotic pathways suggest that the cellular microenvironment may play an important role as well.
Smoking and Sex-Specific Gene Expression
Shriver et al. (p. 24) have analyzed gastrin-releasing peptide receptor (GRPR) messenger RNA (mRNA) expression in lung tissues and cultured airway cells from 78 individuals. This receptor has been associated with the proliferation of bronchial cells exposed to gastrin-releasing peptide and with long-term tobacco use. The investigators found GRPR mRNA expression in more female nonsmokers and short-term (1-25 pack-years) smokers than in the corresponding male subsets. Female smokers exhibited expression of GRPR mRNA at a lower mean pack-year exposure to smoking than male smokers. Since the GRPR gene is located on the X chromosome and escapes X-inactivation, the authors conclude that a second expressed copy of the GRPR gene in women may be responsible for their higher susceptibility to tobacco-induced lung cancer compared with men.
Alternative Therapy and Breast Cancer
Interest in alternative medicine is growing rapidly in the United States. Lee et al. (p. 42) studied the use of alternative therapies by women with breast cancer in four ethnic groups (Latino, white, black, and Chinese) in San Francisco and explored factors influencing the choices of their therapies. They found that about half of the women used at least one type of alternative therapy, and about one third used two types. Blacks most often used spiritual healing (36%), Chinese used herbal remedies (22%) most often, and Latinas used dietary therapies and spiritual healing most often (26%). Among whites, 35% used dietary therapies and 17% used psychological methods. They found that women most likely to use alternative therapies had higher education or income, were younger, had private insurance, and exercised or attended support groups.
"Physicians who treat patients with breast cancer should initiate dialogues on this topic to better understand patients' choices with regard to treatment options."
—Lee et al.
Modeling Tamoxifen's Efficacy
Tamoxifen was shown in the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Trial (BCPT) to reduce the incidence of invasive breast cancer. However, it is not known whether the drug prevents new tumor development, treats occult tumors (those not yet large enough to be detected by mammography), or does both. Radmacher and Simon (p. 48) distinguished tamoxifen's effects on occult and new tumors by using statistical models based on tumor growth rates and breast cancer incidence data from the BCPT. Using models that assume either exponential or size-limited tumor growth, the authors concluded that tamoxifen treats occult disease as well as prevents new tumor formation and growth.
Treating Advanced Prostate Cancer
Androgen withdrawal is currently the only effective form of systemic therapy for advanced prostate cancer. Chemotherapy for this disease, using both experimental and approved agents, has yielded objective response rates of less than 10% and no demonstrated survival benefit. Unfortunately, progression to androgen independence occurs frequently within a few years of androgen withdrawal. Several experimental and clinical studies have implicated increased expression of Bcl-2 protein with the development of androgen resistance and chemoresistance in prostate cancer. In this issue, Miayake et al. (p. 34) demonstrated, by use of a mouse androgen-dependent tumor model, that treatment of tumor cells in vitro with antisense Bcl-2 oligodeoxynucleotides reduced expression of Bcl-2 messenger RNA and increased sensitivity to paclitaxel chemotherapy in a dose-dependent manner. Furthermore, in vivo administration of antisense Bcl-2 oligodeoxynucleotides and paclitaxel delayed progression to androgen independence and inhibited the growth of hormone-refractory tumors compared with either agent alone.
Germ Cell Tumors and Hematologic Neoplasia
Extragonadal germ cell tumors of the mediastinum—the space in the chest between the lungs that contains the heart and other tissues—are rare. Occasionally, diagnosis of these tumors is followed quickly by a diagnosis of leukemia or another hematologic disorder. To learn more about the natural history of this little-known succession of neoplasias, Hartmann et al. (p. 54) studied a series of 635 patients with extragonadal germ cell tumors. Seventeen patients developed a hematologic disorder within 3 years of diagnosis of the primary germ cell tumor; all affected individuals had mediastinal germ cell tumors with nonsemi-nomatous histology. The median survival among the 17 patients (from the diagnosis of the germ cell tumor) was 14 months, compared with a survival of 51 months for patients without hematologic neoplasia. The authors conclude that, based on chromosomal similarities, the two diseases are likely to involve common progenitor cells.
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