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At least 217 records · Page 12Linked to original sources
PubMed1984

Induced and inherent resistance to alkylating agents in human small-cell bronchial carcinoma xenografts.

Inherent and induced resistance was investigated in human small-cell lung cancer xenografts. Specimens from three patients were established in immune suppressed mice; the sensitivity of the xenografts to cyclophosphamide, MeCCNU and melphalan was determined using the growth delay end-point. Clinical chemosensitivity data were available in two cases and inherent differences in sensitivity were noted both in the xenografts and clinically. Radioactively labelled melphalan uptake studies were performed with these two xenografts. A number of different strategies to induce resistance were explored. Only one method proved to be successful and in only one of the xenografts; this was with cyclophosphamide. The induced resistant line was characterised in terms of the time course of its production, the degree of induced resistance, the growth rate, the cross-resistance pattern and stability of the phenotype; the possibility of altered antigenicity was also examined.

Alkylating Agents↗
PubMed1986

Emergence of nitrosourea resistant sublines of Lewis lung tumour following MeCCNU treatment in vivo.

Several different drug retreatment protocols were employed to examine the emergence of resistance to MeCCNU in Lewis lung tumours. Previous studies suggested that although the majority of cells in untreated Lewis lung tumours were sensitive to MeCCNU, there was a very small proportion of resistant cells (approximately 0.001%) that limited "tumour cure' with that drug. If such cells were inherently drug resistant then it should be possible to derive highly resistant tumours by repeated drug treatment. In the first experiment tumours were treated with a single high dose of MeCCNU (35 or 40 mgkg-1) and on regrowth, transplanted into fresh mice and tested for drug sensitivity. Using both excision cell survival and growth delay endpoints, only approximately 25% of tumours were significantly resistant to the test dose, suggesting that many tumours resist the effects of the drug for reasons other than the presence of inherently drug resistant cells. One of the tumours (R4), that regrew after the initial treatment and appeared to be resistant to the test treatment, was retreated with a further 30 mgkg-1 MeCCNU and became more resistant. This line, designated R4/1, was cross-resistant to the other nitrosoureas, BCNU and CCNU, but not to cyclophosphamide, melphalan, cis-platinum or ionising radiation. The effect of treatment dose on the kinetics of MeCCNU resistance development was also studied in a retreatment regimen where the tumours were allowed to regrow and then transplanted into fresh hosts for the next treatment. Resistance developed more quickly at an intermediate dose of 15 mgkg-1 than at 7.5 mgkg-1 where the selective pressure was lower, or at 30 mgkg-1 where there was probably extinction of partially resistant cells. Resistance to MeCCNU developed even more quickly when tumours were retreated several times in the same host, although in a similar experiment with cyclophosphamide no resistance occurred.

Animals↗
PubMed1988

Priming with low doses of methyl-CCNU reduce the toxicity of high doses of methyl-CCNU and melphalan, and increase the lifespan of mice implanted with Lewis lung carcinoma.

Pretreatment of mice with low doses of methyl-CCNU was shown to reduce the toxicity of lethal doses of methyl-CCNU or melphalan administered one or two days following the low dose. There was an increase in survival rate, body weight, thymus and kidney wet weight. Tissue morphology was less affected in the primed mice as compared to mice receiving the high dose or a high-low dose combination. In mice implanted s.c. with Lewis lung carcinoma, priming with 5 mg kg-1 methyl-CCNU 2 days before injection of a very high (35 mg kg-1) dose significantly increased the lifespan as compared to treatment with the high dose alone or with high-low dose combination. When the dose of methyl-CCNU was further increased to 40 mg kg-1 toxic death occurred, which was, however, significantly reduced by 'priming' with the low dose given. When low-high dose combination was used twice (the high dose was given on day 7 or 9, and 18 or 20 after tumour inoculation), priming with 5 mg kg-1 (but not with 10 mg kg-1) two days prior to the high dose was beneficial in reducing toxic death (in two experiments) and either increasing lifespan or not significantly increasing it. In no case was there protection of the tumour by the low-high dose combinations.

Animals↗
PubMed1985

O6-Alkylguanine-DNA alkyltransferase activity correlates with the therapeutic response of human rhabdomyosarcoma xenografts to 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea.

Immune-deprived female CBA/CaJ mice bearing xenografts of six different human rhabdomyosarcoma lines were treated with 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU). Tumor responses were compared with levels of O6-methylguanine-DNA methyltransferase activity because of evidence indicating that repair of DNA interstrand cross-link precursors, mediated by the transferase, may be an important determinant of MeCCNU cytotoxicity. Levels of methyltransferase in tumor extracts were measured by determining the loss of O6-methylguanine from 3H-labeled methylated DNA. Five of the six tumor lines examined showed either no response to MeCCNU or regrowth after an incomplete response. In each instance, the extent of tumor regression correlated with the level of O6-methylguanine-DNA methyltransferase activity in tumor extracts. The single highly drug sensitive line was totally devoid of the activity. These results suggest that O6-methylguanine-DNA methyltransferase levels in human tumor cells may be a clinically useful predictor of sensitivity to the chloroethylnitrosoureas.

Animals↗
PubMed1985

Management of cancer in the elderly. Implications of the aging process.

Cancer is one of the most serious illnesses of the elderly. Screening programs focusing on its early detection in this age-group are needed to allow maximum opportunity for cure. Also important is convincing the older patients who smoke that stopping is still worthwhile. Compared with younger patients, the elderly have more intercurrent medical illnesses and are more likely to suffer from financial difficulties and loss of family support. These factors must be considered when managing these patients. Although age-imposed compromises in treatment are often made, available data suggest that a priori dose reduction of chemotherapy on the basis of age alone is not indicated in patients with solid tumors. Prospective clinical trials are needed to further address the issue of responsiveness to chemotherapy as a function of age. Such trials should include assessment of physiologic age and quality of life.

Aged↗
PubMed2006

Chemoradiotherapy in patients with anal cancer: impact of length of unplanned treatment interruption on outcome.

The aim of this retrospective analysis was to evaluate feasibility and effectiveness of definitive chemoradiotherapy without split-course technique in anal cancer patients. From 1993 to 2003, 81 patients were treated; 13 were excluded due to various chemotherapeutic regimes, thus 68 patients were analysed. In case of acute grade 3 toxicities, treatment was halted until improvement or resolution independent of dose. Short interruption was defined as completing treatment without exceeding eight cumulative treatment days beyond scheduled plan, other patients were considered to have had prolonged interruption. Median follow-up was 46 months. Median overall treatment time was 53 days corresponding to an interruption of eight cumulative treatment days. Thirty-five patients (51%) had treatment interruption of <or=8 days. No acute grade 4 toxicities were observed; one fatality occurred during treatment due to ileus-like symptoms according to acute grade 5 toxicity. Comparing patients with short vs. prolonged interruption 5-year actuarial rates for local control were 85% vs. 81% (p = 0.605) and for colostomy-free survival 85% vs. 87% (p = 0.762), respectively. Chemoradiotherapy with short individualised treatment interruptions seems to be feasible with acceptable acute or late toxicities. Treatment is highly effective in terms of local control and colostomy-free survival.

Adult↗
PubMed2005

FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer.

The FAS receptor-ligand system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumor-immune escape and carcinogenesis. We have recently demonstrated (Sun, T., X. Miao, X. Zhang, W. Tan, P. Xiong, and D. Lin. 2004. J. Natl. Cancer Inst. 96:1030-1036; Zhang, X., X. Miao, T. Sun, W. Tan, S. Qu, P. Xiong, Y. Zhou, and D. Lin. 2005. J. Med. Genet. 42:479-484) that functional polymorphisms in FAS and FAS ligand (FASL) are associated with susceptibility to lung cancer and esophageal cancer; however, the mechanisms underlying this association have not been elucidated. We show that the FAS -1377G, FAS -670A, and FASL -844T variants are expressed more highly on ex vivo-stimulated T cells than the FAS -1377A, FAS -670G, and FASL -844C variants. Moreover, activation-induced cell death (AICD) of T cells carrying the FASL -844C allele was increased. We also found a threefold increased risk of cervical cancer among subjects with the FASL -844CC genotype compared with those with the -844TT genotype in a case-control study in Chinese women. Together, these observations suggest that genetic polymorphisms in the FAS-FASL pathway confer host susceptibility to cervical cancers, which might be caused by immune escape of tumor cells because of enhanced AICD of tumor-specific T cells.

Adult↗
PubMed1978

Mutagenicity of nitrosourea compounds for Salmonella typhimurium.

The nitrosourea derivatives 1,3-bis(2-chloroethyl)-1-nitrosourea (NSC-409962), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; NSC-79037), 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Me-CCNU; NSC-95441), and 1-methyl-1-nitrosourea (MNU; NSC-23909) were screened for mutagenic potential with Salmonella typhimurium strains G46 and TA1530 in vitro and in vivo. Alu were also mutagenic in the host-mediated assay. Four additional chemotherapeutic nitrosoureas were tested in vitro, three of which were mutagenic. The lack of activity of the fourth agent was probably a reflection of its stability in solution rather than a true indication of mutagenic potential. All eight agents were tested in a repair test with S. typhimurium strains TA1978 and TA1538. Results of this test were negative, reflecting the insensitivity of these strains to ethylating and methylating agents. The insensitivity of the host-mediated assay is also discussed.

Carmustine↗