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

We report that p.o. administration of DL-alpha-difluoromethylornithine (DFMO), a specific inhibitor of polyamine biosynthesis, markedly inhibits the growth of established implants of cultured human small cell lung carcinoma (SCC) in athymic (nude) mice. Human SCC tumor cells, from a cell line which exhibited cell death in culture in the presence of DFMO, were inoculated s.c. into athymic mice. The tumors were permitted to grow until they became palpable (0.05 cu cm, 3- to 5-mm-diameter nodules). The animals were then randomized into control, and early (low tumor burden) and late (high tumor burden) treatment groups which received 3% DFMO in the drinking water (5.0 g/kg/day). The tumors in the untreated control group grew to a size of 29 cu cm by 9 weeks, and these animals had a median survival of 9 weeks. The late treatment group began DFMO treatment 3 weeks after clinical tumor engraftment, when mean tumor size was 1.5 cu cm (1.2- to 1.5-cm-diameter nodules). Tumor growth was inhibited by 60% (11.4 cu cm) by Week 9 and survival was prolonged, with 83% survival at 10 weeks and a 56% increase in median survival to 14 weeks (p less than 0.05). The early treatment group received the same dose of DFMO beginning 1 week after tumor engraftment, when their mean tumor size was 0.1 cu cm (4- to 6-mm-diameter nodules). The early DFMO group had a 99% inhibition in tumor growth (0.3 cu cm) (p less than 0.05). Survival was also prolonged compared to the untreated controls, with 83% survival at 10 weeks and a median survival of 15 weeks (p less than 0.05). In both the early- and late-DFMO-treatment groups, no significant clinical toxicities were observed in the first 10 weeks, during which antitumor therapeutic effects were seen. DFMO may have a potential role in the treatment of sensitive human tumors such as SCC. The data suggest that DFMO may be most useful clinically in patients with SCC who have a low tumor burden. Thus, DFMO might be an important tool to produce long-term maintenance of initial clinical remissions induced by combination chemotherapy.
 ...
PMID:Successful treatment with DL-alpha-difluoromethylornithine in established human small cell variant lung carcinoma implants in athymic mice. 640

The combination chemotherapy of water-soluble nitrosourea MCNU with various anti-tumor agents was studied using L1210 leukemia, Lewis lung carcinoma and B16 melanoma. The combinations of MCNU with 5-fluorouracil, cytosine arabinoside, adriamycin, mitomycin C, carboquone or cyclophosphamide produced significantly enhanced anti-tumor effects in L1210 leukemia. By combination with antimetabolites such as 5-fluorouracil or cytosine arabinoside, marked anti-tumor effects were observed over a wide range of dosage. It was suggested that 2-drug combination of MCNU plus 5-fluorouracil or 3-drug combination of MCNU plus 5-fluorouracil and adriamycin was useful in Lewis lung carcinoma or B16 melanoma. From these results, it was recognized that the multiple drug combination chemotherapy of MCNU was therapeutically useful, when given with 5-fluorouracil or cytosine arabinoside.
 ...
PMID:[Effect of combination chemotherapy of nitrosourea MCNU with various anti-tumor agents]. 642 26

It has recently been reported that compounds more lipophilic than misonidazole are better potentiators of CCNU tumor cytotoxicity in vivo. There is now a need to extend these studies to include other tumors and cytotoxic drugs. In the present study we have shown that misonidazole (MISO) can potentiate cyclophosphamide cytotoxicity in the Lewis lung carcinoma but not in the B16 melanoma. Further studies in the Lewis lung carcinoma, using 15 1-substituted 2-nitroimidazoles possessing a range of octanol:water partition coefficient (P) (from 0.18- greater than 100) have shown that potentiation increases with increasing lipophilicity. The most efficient compounds at administered dose levels of 1.0 and 2.0 mumol/g were Ro-07-1902, benznidazole (Ro-07-1051) and RSU 1050 which possess octanol:water partition coefficients in the range of 2.5-10. However, on the basis of an equitoxic administered dose (1/2LD50/2d), little difference in potentiation is seen over the range of P studied.
 ...
PMID:Potentiation of cyclophosphamide cytotoxicity in vivo: a study with misonidazole and fifteen other 1-substituted 2-nitroimidazoles. 648 Apr 52

An activated carbamate, 2-nitrophenyl (2-fluoroethyl)nitrosocarbamate (3), was used to advantage in the synthesis of the water-soluble (2-fluoroethyl)nitrosoureas 6a--d from 2-aminoethanol, (1 alpha, 2 beta, 3 alpha)-2-amino-1,3-cyclohexanediol, cis-2-hydroxycyclohexanol, and 2-amino-2-deoxy-D-glucose. In a variation of this method, 2,4,5-trichlorophenyl (2-fluoroethyl)carbamate (4) was used to prepare the urea from which the essentially water-insoluble N-(2,6-dioxo-3-piperidinyl)-N-(2-fluoroethyl)-N-nitrosourea (6e) was derived. The anticancer activity of these nitrosoureas was determined against the murine tumors B16 melanoma and Lewis lung carcinoma and found to be significant and comparable to their chloroethyl counterparts. On the basis of results from both systems, the dihydroxycyclohexyl derivative 6b may be the most effective.
 ...
PMID:Studies on synthesis and anticancer activity of selected N-(2-fluoroethyl)-N-nitrosoureas. 649 72

A new water-soluble nitrosourea derivative, methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), was tested for antitumor activity against murine tumors (L1210 and P388 leukemias, B16 melanoma, and Lewis lung carcinoma) and BC-47 rat bladder carcinoma, and the results were compared with those for four other nitrosourea derivatives; chlorozotocin, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU), 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1- nitrosourea hydrochloride (ACNU), and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU). MCNU was shown not only to have a broad antitumor spectrum against all the tumors tested, but also to be effective over a wide range of dosages. The antitumor activity of MCNU was superior to those of GANU and chlorozotocin and similar to those of ACNU and methyl-CCNU. Furthermore, MCNU and other nitrosoureas were evaluated for toxicity in BDF1 female mice with respect to body weight changes. Weight loss in mice given MCNU at a dose lethal to 10% of the mice was relatively mild and the treated mice regained body weight most rapidly to the pretreatment level among all groups receiving the above drugs at equitoxic doses. These results may suggest that MCNU is a new nitrosourea derivative worthwhile to perform clinical trials.
 ...
PMID:Antitumor activity and toxicity of methyl 6-[3-(2-chloroethyl)- 3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside in experimental animals. 651 Jun 39

It has been reported that treatment with cimetidine, a histamine H2-receptor antagonist, increased survival and decreased the number of lung metastases in mice bearing the Lewis Lung carcinoma [29]. It was suggested that this effect was due to the ability of cimetidine to block histamine activation of suppressor lymphocytes and hence allow host defence mechanisms to inhibit tumour growth. In the present studies, C3H/He mice were implanted with a C3H mouse mammary adenocarcinoma on Day 0. This tumour metastasizes to the lungs in 30-50 days. Primary tumours were ablated with X-rays when they had grown to about 0.2 g and animals were given drinking water with or without cimetidine (10 mg ml-1) until the end of the experiment. Cimetidine reduced the number of mice dying from metastatic disease from 7/15 (controls) to 3/13. Cimetidine treatment also prolonged survival of mice that did succumb to metastatic disease by about 12 days. The response of spleen lymphocytes to the mitogens phytohaemagglutinin and lipopolysaccharide was assessed in vitro by uptake of 3H-thymidine 0, 16, 45 and 58 days after tumour implantation. Lymphocyte responsiveness was depressed by tumour burden. The influence of cimetidine treatment was equivocal being dependent upon time after tumour implantation and dose of mitogen. In this mouse-tumour system, the mechanism of the antimetastic effect of cimetidine is different from that previously suggested [29].
 ...
PMID:Antimetastatic effect of cimetidine on mice bearing a C3H mouse mammary adenocarcinoma: survival and lymphocyte function studies. 654 88

The water-soluble peptidoglycan monomer (PGM) isolated from the culture fluid of Brevibacterium divaricatum, which has immunostimulating activity, has been examined for its antitumor effects in C57BL mice bearing Lewis lung carcinoma. The formation of spontaneous lung metastases from SC tumor implants is significantly inhibited. The growth of SC primary tumors, including advanced ones, is also significantly inhibited, though to a less pronounced extent than the growth of metastases. The effects on metastases are evident with all treatment schedules used, whereas those on SC primary tumors are treatment schedule-dependent. The treatment with PGM was found to be therapeutically useful when combined with surgical removal of IM implants; in conditions where a single post-operative treatment was ineffective, combined post-operative and immediately pre-operative administration of PGM significantly increased (by 40%) the survival time of treated animals over that of controls undergoing surgery only.
 ...
PMID:Immunotherapy of Lewis lung carcinoma with hydrosoluble peptidoglycan monomer (PGM). 655 16

The treatment of mice bearing i.m. B16 melanoma with equitoxic dosages of the clinically used 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) and of its benzenoid water-soluble analogue p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt (DM-COOK) prior to surgical tumor removal results in a remarkable proportion of cures, even when the treatment is started on already palpable tumors for which surgery alone is ineffective. The survival time of mice which are not cured is also significantly increased with DM-COOK. At the same time, DM-COOK does not affect artificial metastases or spontaneous metastases in mice undergoing surgery and treated with DM-COOK postoperatively. Inhibition of i.m. tumor growth in surgical experiments, and of s.c. tumors in mice not treated with surgery, is significant, although not as pronounced as is necessary to obtain significant prolongation of the life span of the host; the survival time of mice with s.c. tumors treated with both drugs is indeed not significantly increased. DM-COOK thus appears to exert selective antimetastatic effects, unrelated to cytotoxicity for tumor cells, against B16 melanoma in addition to those reported for Lewis lung carcinoma and M5 ovarian reticular cell sarcoma; its therapeutic usefulness is evidenced in adjuvant surgical experiments. DM-COOK, unlike DTIC, is devoid of hematological toxicity for the host. Since, in leukemic mice, it is at least as active as DTIC in increasing the life span of the treated animals, it appears to be an advantageous substitute for DTIC that could undergo preliminary clinical trial.
 ...
PMID:Antimetastatic action and hematological toxicity of p-(3,3-dimethyl-1-triazeno)benzoic acid potassium salt and 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide used as prophylactic adjuvants to surgical tumor removal in mice bearing B16 melanoma. 669 62

Antitumor activities of a combination chemotherapy with a water-soluble nitrosourea, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), and a single dose of 6-thioguanine were studied using three obstinate murine tumor systems, i.e., Lewis lung carcinoma, B16 melanoma, and an advanced stage of L1210 leukemia systems. Therapeutically synergistic effect was observed either definitely against 1- or 2-day-old Lewis lung carcinoma and 6-day-old L1210 leukemia or moderately against 1-day-old B16 melanoma. Single intravenous treatment on day 7 after subcutaneous implantation of Lewis lung carcinoma, when the tumors had already metastasized to the lungs, produced a significant regression of tumor and a significant increment in survival time of tumor-bearing mice. In comparative studies, the combination of ACNU and 6-thioguanine showed a greater and a wider spectrum of antitumor activities against these tumors than those obtained by the combination with ACNU and a single dose of 5-fluorouracil, methotrexate, or 6-mercaptopurine. Increment in lethal toxicity for normal and tumor-bearing mice was not observed by the combination of ACNU and 6-thioguanine in contrast to definite increases in this toxicity by the combination of ACNU and 5-fluorouracil. The present experimental results may suggest the clinical utility of the combination chemotherapy with ACNU and 6-thioguanine in the treatment of several solid tumors as well as acute leukemias.
 ...
PMID:Potentiation of therapeutic effects of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride by 6-thioguanine in mouse tumor systems: comparison with other antimetabolites. 692 70

The physiological disposition of N-(phosphonacetyl)-L-aspartate (NSC 224131; PALA), a potent inhibitor of aspartate transcarbamylase, has been studied in mouse, rat, dog, and monkey after administration of [14C]PALA at 120 mg/sq m i.v. or p.o. Concentrations of PALA equivalents in plasma, urine, and feces were determined radiochemically, and urine was analyzed chromatographically for PALA. The disposition of PALA equivalents in mouse tissues was determined radioautographically. After i.v. administration, PALA was rapidly (half-time, approximately 1 hr) and extensively (up to 80% of the dose) excreted in the urine of all species. Less than 5% was excreted in the feces. Only PALA was found in the urine of all four species, indicating that the metabolism of PALA, if it occurs at all, is insignificant. PALA equivalents were poorly taken up by mouse tumors and tissues, except kidney, bone, and to a lesser extent, skin and lung, and were rapidly and extensively cleared from all except bone. No differences were apparent in the uptake of PALA equivalents by Lewis lung carcinoma (sensitive to PALA treatment) and L1210 lymphocytic leukemia (insensitive). The pharmacokinetics of PALA in the plasma of rat, dog, and monkey, as well as mouse, were inconsistent with deposition of PALA in tissues and more consistent with the probable distribution of PALA into extracellular water. PALA equivalents were eliminate from all species at a rate (half-time, 1 to 1.5 hr) reflecting the rate of urinary excretion of the drug and at a secondary slower rate probably reflecting the rate of release of bound PALA from sites such as aspartate transcarbamylase. PALA was poorly absorbed into the systemic circulation when administered p.o., in that mouse, rat, and monkey excreted less than 5% of the dose in the urine after p.o. administration. These data on the physiological disposition of PALA explain why high doses of the drug have to be administered to achieve therapeutic and toxic effects, despite the inhibitory potency of the drug on aspartate transcarbamylase. They indicate that PALA will be ineffective administered p.o. and might be contraindicated in patients with impaired renal function and that the kinetics of aspartate transcarbamylase-bound drug is probably more important in determining dose scheduling than the kinetics of free PALA.
 ...
PMID:Comparative physiological disposition of N-(phosphonacetyl)-L-aspartate in several animal species after intravenous and oral administration. 705 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>