Cancer research
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Clinical strategies which modulate the human anti-mouse antibody response (HAMA) in patients may have a profound influence on the idiotype network inducible by murine monoclonal antibodies (MoAb). Prior to myeloablative chemotherapy (ABMT), 9 patients with Stage IV neuroblastoma were imaged with 131I-3F8, a MoAb specific for the ganglioside GD2. Their serum HAMA, anti-idiotypic, anti-GD2, and anti-anti-idiotypic antibodies were assayed by enzyme-linked immunosorbent assay prior to, and at 3 and 6 months postimaging. ⋯ Five of the 9 patients are long-term survivors; all had elevated anti-GD2 and anti-anti-idiotypic levels, significantly higher than those who died of disease. Although 131I-3F8 imaging prior to ABMT detected abnormal sites in 4 of 9 patients, 3 of the 4 patients have continued in remission for 24-63 months after ABMT, and all 3 mounted anti-GD2 and anti-anti-idiotypic antibody responses. We conclude that myeloablative therapy strongly suppressed the HAMA/anti-idiotypic response to murine MoAb and that the prognostic significance of host immune response to ganglioside GD2 MoAb deserves further investigation.
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The basic cancer-related chemical and biological sciences, pathology, and epidemiology have contributed to the understanding that antimutagenesis and antiproliferation are the important general mechanisms of chemoprevention and to the development of antimutagenic and anti-proliferative agents as potential chemopreventive drugs. These disciplines have also provided the biochemical and histopathological bases for identifying intermediate biomarkers that can be used as surrogate end points for cancer incidence in clinical chemoprevention trials and for selecting cohorts for these trials. Particularly important as histological biomarkers of cancer are the cytonuclear morphological and densitometric changes that define intraepithelial neoplasia (IEN). ⋯ Presurgical breast cancer patients and patients with ductal or lobular carcinoma in situ are cohorts for studies in breast. Patients with superficial bladder cancers (Ta/T1 with or without carcinoma in situ) are cohorts for studies of chemoprevention in bladder, and patients with dysplastic oral leukoplakia are evaluated for chemoprevention of oral cancers. Cervical intraepithelial neoplasia is a prototype IEN, and patients with cervical intraepithelial neoplasia are a cohort for studies of cervical cancer.
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Tobacco-specific nitrosamines are a group of carcinogens formed from nicotine and related tobacco alkaloids. Two of these compounds, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine, are believed to be involved as causative agents for cancers of the lung, oral cavity, esophagus, and pancreas associated with the use of tobacco products. The goal of the studies described here is to develop biomarkers which will allow us to understand the uptake, metabolic activation, and detoxification of these carcinogens in humans. ⋯ A subset of smokers and most tobacco chewers have hemoglobin adduct levels which are higher than detected in nonsmokers. 4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts are higher in lung tissue from smokers than from nonsmokers. These data indicate that some smokers and tobacco chewers are capable of metabolically activating NNK or N'-nitrosonornicotine to intermediates which bind to cellular macromolecules and are, therefore, at potentially higher risk for cancer development. The application of these biomarkers to studies on cancer induction by tobacco products is discussed.
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The search for compounds active against solid tumors has led us to the discovery of a novel sulfonamide, E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzenesulfonamide), which inhibits tubulin polymerization. When administered orally, E7010 showed good antitumor activity against various rodent tumors and human tumor xenografts. In tests on mouse tumor, E7010, administered in doses of 25-100 mg/kg daily for 8 days, inhibited the growth of colon 38 carcinoma inoculated s.c. in mice by 60-99%. ⋯ E7010 inhibited the growth of: four kinds of gastric cancer, H-81, H-111, SC-2, and SC-6 by 60-78%; three kinds of colon cancer, H-143, COLO320DM, and WiDr by 58-83%; three kinds of lung cancer, LC-376, LC-6, and LX-1 by 63-82%; and two kinds of breast cancer, H-31 and MX-1 by 79-87%. In studies on drug-resistant P388 leukemia, E7010 was effective against vincristine-resistant P388, cisplatin-resistant P388, and 5-fluorouracil-resistant P388 sublines in mice. Because of its good activity against rodent tumors and human tumor xenografts, E7010 is currently undergoing Phase I clinical trials.