© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 23, 1979,
December 1, 1999
© 1999 Oxford University Press
IN THIS ISSUE |
Can dying cells from a patient's tumor serve as an anticancer vaccine? To explore this possibility, Pierrefite-Carle et al. (p. 2014) created "suicide" tumor cells by introducing the Escherichia coli cytosine deaminase gene into cells of a rat colon carcinoma cell line. Exposure of the modified cells to the nontoxic compound 5-fluorocytosine causes them to die because the bacterial gene product converts it into the cytotoxic agent 5-fluorouracil. When the modified cells are injected into the livers of syngeneic animals, they form single experimental "suicide tumors." As expected, when animals bearing suicide tumors were treated with 5-fluorocytosine, substantial tumor regression was observed. However, when animals were injected with the modified cells in one liver lobe and treated with 5-fluorocytosine, they appeared resistant to the establishment of wild-type colon tumors in the other liver lobe or exhibited regression of pre-existing wild-type tumors. The authors discovered that this distant bystander effect involved the action of natural killer lymphocytes.
In an accompanying editorial, Morris (p. 1986) places the study of Pierrefite-Carle et al. in the context of prior research on "suicide" gene therapy for cancer. He notes the immunologic basis for the observed "bystander effect at a distance" and comments on the finding by the investigators that it is generated by NK cell activity rather than CD8+ lymphocytes. He suggests that generation of a clinically meaningful antitumor vaccine requires enhanced delivery and activity of such enzyme/prodrug systems to improve local tumor cell killing.
Danger to Nonsmokers
To investigate whether the genotype of a never smoker exposed to environmental tobacco smoke (ETS) influences the risk of lung cancer, Bennett et al. (p. 2009) analyzed tumor tissues from 106 white Missouri women with lung cancer who were enrolled in a case-control study of ETS (and other personal and environmental factors) and lung cancer risk. By looking at inherited variants (polymorphisms) in three genes associated with the activation or detoxification of tobacco smoke carcinogens, the researchers found that a common genetic polymorphism in the glutathione S-transferase M1 (GSTM1) gene divided this population of never smokers into equal-sized groups, one with a higher risk of lung cancer associated with ETS exposure than the other. The high-risk group consisted of women in whom both copies of the GSTM1 gene were deleted, while the lower risk group contained women with one or two normal gene copies.
In an accompanying editorial, Weinberg and Sandler (p. 1985) note that, while the case-only analysis used by Bennett et al. has some important advantages, it also has limitations. In addition, the editorialists discuss potential biases in the study. They conclude that the magnitude of the interaction between ETS and the GSTM1 genotype reported by Bennett et al. requires confirmation.
Mercaptopurine Therapy Intolerance
Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those who are homozygously deficient in thiopurine S-methyltransferase (TPMT) enzyme activity demonstrate an extreme sensitivity to this drug, due to the accumulation of higher cellular concentrations of thioguanine nucleotides. Relling et al. (p. 2001) studied 6-mercaptopurine metabolism, dose requirements, and tolerance among patients of different TPMT phenotypes. Thioguanine nucleotide concentrations in erythrocytes and TPMT enzyme activity showed an inverse relationship. The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest in the two patients who were homozygous for TPMT mutations (both required dose reduction), intermediate among the 17 who were heterozygous (35% required dose reduction), and lowest among the 161 who were wild-type (7% required dose reduction). Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in TPMT-deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations. The investigators recommend pretherapy determination of TPMT status in patients who are candidates for treatment with mercaptopurine.
In an editorial, Balis and Adamson (p. 1983) note that categorizing patients according to the genotype may prospectively identify subsets of patients who would be less tolerant of anticancer drugs, but for relatively uncommon enzyme polymorphisms/mutations this will only identify a small subset of patients who would benefit from pharmacogenetically guided dosing. In contrast, they say that phenotyping patients by estimating enzyme activities may also allow for individualized drug dosing among patients with a homozygous wild-type genotype. This study illustrates the potential utility of a pharmacogenetic approach in prospectively defining subsets of patients who may be less tolerant of anticancer drugs, Balis and Adamson say.
Missed by Mammography?
Although mammographic screening is useful for detecting early breast cancer, some tumors are missed and subsequently come to attention after a normal screening examination. Some of these tumors may be too small to be detected at the time of mammography but then grow quickly to a palpable size; others may have physical features that make them difficult to detect mammographically. Porter et al. (p. 2020), working with a defined population of women enrolled in a high-quality screening program in a health maintenance organization, compared the biologic characteristics of breast tumors detected at the time of mammography with those detected between screening examinations. They found that young women were more likely to have interval-detected cancers and that tumors with more aggressive features were also more likely to surface between screening examinations than tumors with less aggressive features. Data such as these can provide background information in the development of optimal screening intervals for specific groups of women.
Early Detection of Renal Cancer
Eisenberger et al. (p. 2028) have investigated the possibility of developing a noninvasive test for the early detection of renal cancer based on an analysis of DNA (microsatellite DNA) from the urine and serum of patients. Such an analysis using a variety of microsatellite DNA markers showed that patients with organ-confined malignant tumors had one or more DNA alterations in their urine and serum samples, while patients with organ-confined masses of low malignant potential displayed alterations in their urine but not in their serum. The authors suggest that DNA analysis of urine specimens may help in the early detection of resectable kidney cancer.
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