Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A nitrogen mustard analog of propranolol was synthesized as a potential lung-specific antitumor agent. Since dl-propranolol concentrates in lung tissue and beta-blocking activity resides only with the l-enantiomer, the d-modification could serve as a lung-directed carrier for a cytotoxic group. Reaction of 1-(1-naphthyloxy)-3-[bis(2-hydroxyethyl)amino]-2-propanol with thionyl chloride resulted in replacement of all three hydroxyl groups with chlorine. The necessary chlorination selectivity was achieved with p-toluenesulfonyl chloride in dimethylformamide solution to provide propranolol mustard, 1-(1-naphthyloxy)-3-[bis(2-chloroethyl)amino]-2-propanol. Both the trichloro compound and propranolol mustard showed reproducible activity against P-388 leukemia. Neither compound was active against the B16 tumor or Lewis lung carcinoma.
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PMID:Synthesis of propranolol mustard as a possible lung-specific antitumor agent. 735 22

We examine the origins of surgical therapy, radiotherapy, and chemotherapy as they were applied to lung cancer in the mid-portion of this century. Surgical therapy for lung cancer started in the 1930s with pneumonectomies. The prognostic significance of nodal metastases was soon recognized, and surgical staging procedures became an important part of patient workup. Radical radiotherapy for potential cure of lung cancer began in the 1950s with megavoltage linear accelerators. The first application of chemotherapy for lung cancer was the use of nitrogen mustards in the 1940s. Single modality surgical therapy has become the treatment of choice for Stages I and II non-small cell lung cancer, but 50% of clinical Stage I patients die of recurrent disease, and 70% of those recur outside the chest. Biologic markers may identify high risk subgroups of Stage I and II patients who may benefit from adjuvant chemo- or radiotherapy. Within the last decade, several single and multi-institutional Phase II trials and two single institution Phase III trials have reported improved survival in Stage IIIA patients treated with cisplatin-based neoadjuvant chemotherapy prior to surgical resection. These trials have reported high response and resectability rates, but at a substantial toxicity. A new standard of care for Stage IIIA disease has not been conclusively established.
Lung Cancer 1995 Jun
PMID:An historical perspective of multi-modality treatment for resectable non-small cell lung cancer. 755 46

Novel pyrrolo[2,3-d]pyrimidine antifolates (1a, b and 2a, b) with a nitrogen atom in the bridge chain between the 2,4-diaminopyrrolo[2,3-d]pyrimidine and phenylene rings were designed and efficiently synthesized. These compounds exhibited more potent inhibitory activities than methotrexate (MTX) against the proliferation of human epidermoid carcinoma KB cells and human non-small cell lung carcinoma A549 cells despite their modest dihydrofolate reductase (DHFR)-inhibitory potency.
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PMID:Synthesis and antitumor activity of pyrrolo[2,3-d]pyrimidine antifolates with a bridge chain containing a nitrogen atom. 772 32

Chinese females in Hong Kong, where only about a third of the lung cancer cases can be attributed to a history of active smoking, have a world age-standardized lung cancer incidence rate of 32.6 per 100 000, which is among the highest in the world. Trends in Hong Kong's female lung cancer mortality also indicate a tripling in mortality rates from 1961 to 1990. The characteristically high Chinese female lung cancer incidence among nonsmokers is also found among overseas Chinese communities in Singapore and Hawaii. To help elucidate the role of ingested and inhaled substances in the etiology of lung cancer, four epidemiological studies have been conducted in Hong Kong over the last 15 years: (1) a retrospective study of 200 cases and 200 neighbourhood controls, (2) a cross-sectional study measuring personal exposures to nitrogen dioxide among 362 children and their mothers, (3) a site monitoring study of 33 homes measuring airborne carcinogens, and (4) a telephone survey of 500 women on their dietary habits and exposure to air pollutants. Selected data from each study were drawn to evaluate exposures to three major air pollutants (environmental tobacco smoke, incense, and cooking fumes), their relationship with lung cancer risk, and their association with dietary habits. Generally in this population, nutritionally poorer diets were characterized by higher consumption of alcohol and preserved/cured foods, whereas better diets were characterized by higher intakes of fresh fruits, vegetables, and fish. For environmental tobacco smoke, exposure was only moderately high in Hong Kong (36% have current smokers at home), lung cancer risk was equivocal with exposure, and it was associated with poorer diets among wives with smoking husbands. Incense was identified as a major source of exposure to nitrogen dioxide and airborne carcinogens, but it had no effect on lung cancer risk among nonsmokers and significantly reduced risk (trend, P-value = 0.01) among smokers, even after adjusting for smoking. The last finding may be explained by the relatively better diets among smoking women who burned incense versus those who did not. Although about 94% of the Chinese women cook on a regular basis, and the cooking fires were associated with increased airborne carcinogens, nonsmoking women who cooked for more than 25 years had a 60% reduction in lung cancer risk and the trend was highly significant (P < 0.001). Again, this unexpected finding may be due to the confounding effects of diet. Female controls who cooked for more than 25 years had a poorer diet than those who cooked for shorter durations. These three examples were chosen to illustrate the complexities of assessing air pollution exposure, and understanding the behavioral and dietary dynamics underlying lung cancer risk assessments. Our conclusion is that diet can be an important confounding factor affecting lung cancer risk estimates from air pollution exposures among Chinese women living in an affluent urban environment.
Lung Cancer 1996 Mar
PMID:Diet as a confounder of the association between air pollution and female lung cancer: Hong Kong studies on exposures to environmental tobacco smoke, incense, and cooking fumes as examples. 878 67

The elemental composition of a variety of tumor samples, including squamous cell lung carcinoma, sarcoma, adenoid cystic carcinoma, melanoma, and rectal carcinoma have been measured by combustion analysis. Hydrogen, carbon, nitrogen, and oxygen content have been determined. Using the elemental neutron kerma data published in ICRU Report #46 the neutron kerma factors for the various tumor samples have been calculated in the energy range 11 eV to 29 MeV. The average neutron kerma values for all tumor samples are approximately 6%-7% lower than those for average soft tissue in the energy range of interest in fast neutron therapy (energies > 1 MeV).
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PMID:The elemental composition of tumors: kerma data for neutrons. 928 46

In mice, 4-nitrobenzylidene malononitrile (AG1714), which belongs to the tyrphostin family, reduced toxicity induced by doxorubicin and cisplatin without impairing their antitumor efficacy. AG1714 reduced mortality induced by doxorubicin and cisplatin. It prevented, in a dose-dependent manner, cisplatin-induced nephrotoxicity as assessed by measurement of serum creatinine and blood urea nitrogen levels. The protective effect of AG1714 was most pronounced on its administration 2 h before cisplatin. AG1714 also prevented doxorubicin-induced myelosuppression as assessed by the scoring of bone marrow nucleated cells and colony-forming units. Cisplatin-induced small intestinal injury was also protected by AG1714 as assessed by histopathological analysis. In vitro, AG1714 reduced cisplatin-induced apoptosis in a murine fibroblastic cell line (A9) and did not affect doxorubicin-induced apoptosis of B-16 melanoma cells. In contrast to its protective effect against mortality and injury of normal tissues induced by chemotherapy, AG1714 did not impair its antitumor activity and in some tumor models enhanced it. This was evident by using the murine tumors B-16 melanoma, Lewis lung carcinoma, and methylcholanthrene-induced fibrosarcoma and the human tumors SK-28 melanoma and human ovary carcinoma xenografts in nude mice. Experiments in which low and high doses of cisplatin and doxorubicin were administered to tumor-bearing mice demonstrated that AG1714 reduced mortality of high-dose chemotherapy and increased its therapeutic index. AG1714 could provide a novel, useful tool to improve chemotherapy by allowing dose intensification.
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PMID:Tyrphostin 4-nitrobenzylidene malononitrile reduces chemotherapy toxicity without impairing efficacy. 962 80

Conjugates of the L49 monoclonal antibody (binds to the p97 antigen on melanomas and carcinomas) were formed by attaching Enterobacter cloacae beta-lactamase (bL) to the L49-Fab' fragment using a heterobifunctional cross-linking reagent or by linking the enzyme to L49-sFv using DNA recombinant technology. The conjugates thus formed, L49-Fab'-bL and L49-sFv-bL, were designed to activate cephalosporin containing anticancer prodrugs at the surfaces of antigen positive tumor cells. Results from in vitro experiments using two lung carcinoma cell lines demonstrated that the conjugates were equally active in effecting the release of phenylenediamine mustard from the cephalosporin nitrogen mustard prodrug CCM. While treatment with either of the conjugates combined with the maximum tolerated doses of CCM led to cures of established SN12P renal cell carcinoma tumors in nude mice, only the L49-sFv-bL conjugate maintained its ability to do so at 1/4 the maximum tolerated dose of CCM. L49-sFv-bL was also superior to L49-Fab'-bL in the 1934J renal cell carcinoma tumor model and was shown to be quite active in two in vivo models of human lung carcinoma. These results demonstrate that the recombinant fusion protein leads to more pronounced therapeutic windows than the chemical conjugate and is active in an array of human tumor models.
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PMID:Comparison of recombinant and synthetically formed monoclonal antibody-beta-lactamase conjugates for anticancer prodrug activation. 1056 79

The lignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of their semisynthetic derivatives, etoposide and teniposide. The latter are included in a wide variety of cancer chemotherapy protocols. Due to these biological activities, lignans, and especially cyclolignans, have been the objective of numerous studies focused to prepare better and safer anticancer drugs. The mechanism by which podophyllotoxin blocks cell division is related to its inhibition of microtubule assembly in the mitotic apparatus. However, etoposide and teniposide were shown not to be inhibitors of microtubule assembly which suggested that their antitumor properties were due to another mechanism of action, via their interaction with DNA and inhibition of DNA topoisomerase II. Other podophyllotoxin derivatives has also been reported which retained or even improved the cytotoxic activity, but these were weak inhibitors of topoisomerase II in vitro; the data revealed that such analogs exhibit a different, as yet unknown, mechanism of action. The main deficiency of these compounds is their cytotoxicity for normal cells and hence side effects derived from their lack of selectivity against tumoral cells. In this regard it is necessary to investigate and prepare new more potent and less toxic analogs, that is, with better therapeutic indices. It is well accepted from structure-activity studies in this field that the trans-lactones are more potent as antineoplastics than the cis-lactones. Not only the configuration of the D ring is an important factor for high cytotoxic activity, but also a quasi-axial arrangement of the E ring is necessary. On this basis, studies on lignans have been addressed to modify the lactone moiety and prepare analogs with heteroatoms at different positions of the cyclolignan skeleton. Our group has been working during the last few years on chemical transformations of podophyllotoxin and analogs and we have prepared a large number of cyclolignan derivatives some of which display potent antiviral, immunosuppressive and cytotoxic activities. We have reported several new cytotoxic agents with nitrogen atoms at C-7 or C-9 or at both C-7 and C-9: imine derivatives, oxime derivatives, pyrazoline-, pyrazo- and isoxazoline-fused cyclolignans. At present, we are preparing mainly new compounds by modifications of the A and E cyclolignan-rings. They are being tested on cultures of different tumoral cell lines (P-388 murine leukemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma) and some of them have shown an interesting and selective cytotoxicity.
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PMID:Antitumor properties of podophyllotoxin and related compounds. 1110 64

We investigated the effects of two newly synthesized steroidal derivatives of nitrogen mustard on sister chromatid exchange rates and on human lymphocyte proliferation kinetics. The compound 33-hydroxy-5alpha,22alpha-spirostan- 12-one-p-(N,N-bis(2-chloroethyl)amino)phenylacetate(1) was, on a molar basis, less effective in inducing sister chromatid exchange and suppressing cell proliferation rate indices than compound 3beta-hydroxy-12alpha-aza-C-homo-5alpha,22alpha-spirostan-12-one-p-(N,N-bis(2-chloroethyl)amino)phenylacetate(2). A correlation was observed between the magnitude of the sister chromatid exchange response and the depression of cell proliferation index. We also studied the effects of the aforementioned compounds on Lewis lung carcinoma. The order of the percent inhibition of tumor growth achieved by the compounds coincides with the order of the cytogenetic effects they induce.
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PMID:A comparative study on cytogenetic and antineoplastic effects induced by two modified steroidal alkylating agents. 1153 Oct 14

The p53 tumor suppressor gene is mutated in about half of all human cancer cases. The p53 protein modulates multiple cellular functions, such as gene transcription, DNA synthesis and repair, cell cycle arrest, senescence, and apoptosis. Mutations in the p53 gene can abrogate these functions and may lead to genetic instability and progress to cancer. The molecular archeology of the p53 mutation spectrum generates hypotheses concerning the etiology and molecular pathogenesis of cancer. The spectrum of somatic mutations in the p53 gene implicates environmental carcinogens and endogenous processes in the etiology of human cancer. The presence of a characteristic p53 mutation also can manifest a molecular link between exposure to a particular carcinogen and a specific type of human cancer, e.g. aflatoxin B1 (AFB1) exposure and codon 249ser mutations in hepatocellular carcinoma, ultraviolet (UV) exposure and CC to TT tandem mutations in skin cancer, and cigarette smoke and the prevalence of G to T transversions in lung cancer. Although several different exogenous carcinogens have been shown to selectively target p53, evidence supporting the endogenous insult of p53 from oxyradical and nitrogen-oxyradicals is accumulating. p53 mutations can be a biomarker of carcinogen effect. Determining the characteristic p53 mutation load in nontumorous tissue, with a highly sensitive mutation assay, can indicate a specific carcinogen exposure and also may help in identifying individuals at an increased risk of cancer.
Lung Cancer 2001 Dec
PMID:Tumor suppressor genes: at the crossroads of molecular carcinogenesis, molecular epidemiology and human risk assessment. 1172 Jul 36


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