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)

From the time of its inception in 1955, the Drug Development Program of the National Cancer Institute has relied primarily on transplanted rodent tumor systems in vivo for the evaluation and selection of potential antitumor agents. Although greater emphasis has been placed in recent years on rationally designed drugs, the major effort throughout the history of the program has involved the empirical screening of a wide variety of chemical structures and natural products of varying sources. The initial screening spectrum consisted of three mouse tumors, Sarcoma 180, Carcinoma 755 and Leukemia 1210, based on the retrospective analysis presented in the GELLHORN-HIRSCHBERG Report. As a result of further expermental studies and analyses, the screens changed successively to (1) L1210 plus a spectrum of mouse, rat and hamster tumors, (2) L1210 plus the rat tumor, WALKER 256, (3) L1210, plus P388 for natural products and B16 melanoma and LEWIS lung carcinoma for special studies, and finally (4) P388 as a pre-screen followed by a panel of transplanted tumors and xenografts representing the major tumor sites. The rationale underlying each of the successive changes, and results obtained with each approach, will be discussed.
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PMID:Antitumor screening procedures of the National Cancer Institute. 61 10

A phase Ilate/II trial of hyperfractionated (HFX) radiation therapy for non-small-cell carcinoma of the lung (NSCCL) was conducted by the Radiation Therapy Oncology Group (RTOG) between 1983 and 1987. Fractions of 1.2 Gy were administered twice daily with greater than or equal to 4 hours between fractions. Patients were randomized to receive minimum total doses of 60.0, 64.8, and 69.6 Gy. After acceptable risks of acute and late effects were found, 74.4 Gy and 79.2 Gy arms were added, and the lowest total dose arms were closed. No significant differences in the risks of acute or late effects in normal tissues were found among the 848 patients analyzed in the five arms; risks of severe or life-threatening pneumonitis were 2.6% for 60.0 to 64.8 Gy, 5.7% for 69.6 to 74.4 Gy, and 8.1% for 79.2 Gy. Among 350 patients who had the same criteria as Cancer and Leukemia Group B (CALGB) protocol 84-33 (American Joint Committee on Cancer Staging [AJCCS], 1984, stage III; Karnofsky performance status [KPS] 70 to 100; less than 6% weight loss), there was a dose response for survival: survival with 69.6 Gy (median, 13.0 months; 2 years, 29%) was significantly (P = .02) better than the lower total doses. There were no differences in survival among the three highest total-dose arms. Comparisons with results in similar patients treated with 60 Gy in 30 fractions of 2.0 Gy 5 days per week for 6 weeks suggest benefit from HFX radiation therapy with 69.6 Gy. Improvement in survival with HFX radiation therapy at 69.6 Gy total dose without increase in normal tissue effects, justifies phase III comparison with standard fractionation alone and combined with systemic chemotherapy in this common presentation of NSCCL.
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PMID:A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11. 216 52

Limited-extent small-cell lung carcinoma (SCLC) remains a therapeutic problem with little improvement in complete response (CR) rates and long-term survival in the past 5 years. From June 1984 through January 1985, 56 patients with limited-extent SCLC were enrolled in a Cancer and Leukemia Group B (CALGB) phase II study using five cycles of cyclophosphamide (500 mg/m2 intravenously [IV] day 1), etoposide (80 mg/m2 IV days 1 to 3), and cisplatin (33 mg/m2 IV days 1 to 3) administered at 3-week intervals (CEP), with radiation therapy (50 Gy to chest and 30 Gy to brain) administered concomitant with cycles 4 and 5, followed by three cycles of cyclophosphamide (500 mg/m2 IV day 1), etoposide (80 mg/m2 IV days 1 to 3), and doxorubicin (50 mg/m2 IV day 1). Of 49 patients evaluable for response, the overall response rate was 88%, with 57% CRs. The median overall survival was 14 months; the median duration of CR was 10 months, and nine CRs remain disease free at a median follow-up of 23 months. Toxicity was significant: 56% patients experienced WBC less than 1,000 microL, 32% platelets less than 25,000 microL and 10% hemoglobin less than 7 g/dL. There was one treatment-related septic death. These results are as good as the best previous CALGB study of SCLC, despite a reduction in duration of treatment from 18 to 5 months. We are currently using a variant of this multimodality treatment approach as our standard management for patients with limited-extent SCLC.
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PMID:A phase II trial of cyclophosphamide, etoposide, and cisplatin with combined chest and brain radiotherapy in limited small-cell lung cancer: a Cancer and Leukemia Group B Study. 282 9

Recurrent or persistent small-cell carcinoma of the lung (SCCL) after chemotherapy (CT) alone has shown a poor response to conventional salvage radiotherapy (RT). Accelerated RT is judged more effective than conventional RT for rapidly growing tumors such as SCCL. The objectives of this study were: to determine the tolerability of accelerated RT; and to test the ability of accelerated RT plus CT to achieve local tumor control (LTC) of SCCL recurrent after CT. Patients whose localized tumor was not controlled were selected from Arm III of the Cancer and Leukemia Group B (CALGB) protocol 8083 (Proc. ASCO 2:230, 1984) as eligible for this study. The program of accelerated RT consisted of the delivery of 50.1 Gray (Gy) in 30 fractions over a period of 21 days to the chest. New chemotherapy different from the first began 2 weeks after the completion of RT and was repeated every 3 weeks for 18 months (M). Of 29 potentially eligible patients with locally recurrent SCCL after the first line CT alone from Arm III of the CALBG protocol 8083, 12 were enrolled initially in this study. The analysis of LTC included 11 patients excluding one patient who died 4 weeks after the start of RT from liver metastases. The LTC achieved was as follow: complete remission in 8/11 (72%) and partial remission in 3/11 patients. None of the patients was converted to CR by subsequent chemotherapy. Survival ranged from 2 to 20 M, with a median survival time of 6 M. Tolerance to the subsequent CT, normal tissue reaction to accelerated RT, and the theoretical advantage of accelerated RT over conventional RT for SCCL were evaluated.
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PMID:Accelerated radiotherapy followed by chemotherapy for locally recurrent small-cell carcinoma of the lung. A phase II study of Cancer and Leukemia Group B. 302 96

Saframycins Yd-1 and Y3, which have an amino functional group in the side chain, were recently obtained by a directed biosynthesis. Twenty-eight side chain-modified chemical derivatives were prepared from these saframycins, and their in vitro and in vivo antitumor activities were studied. Among these new derivatives, three saframycins, namely, two N-acyl derivatives, pivaloyl- and n-caproylsaframycin Y3, and one water-soluble type, saframycin Yd-1.HCl, were found to show marked antitumor activity against L1210 mouse leukemia cells. Further studies of these saframycin derivatives using B16-F10 melanoma and Lewis lung carcinoma indicated that all three saframycins are also active against B16-F10 melanoma; saframycin Yd-1.HCl showed the greatest prolongation of survival time. Marked inhibition of spontaneous metastasis of Lewis lung carcinoma was observed in mice treated with these new derivatives. Structure-activity relationships among these semisynthetic saframycins are discussed.
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PMID:Antitumor activity of new semisynthetic saframycin derivatives. 309 20

This study examined the association between two primary covariates, extent of disease (ED) and performance status rating (PSR), and the outcome of psychological distress in patients with small cell carcinoma of the lung. Patients were studied at the time of entry onto one of three Cancer and Leukemia Group B (CALGB) protocols: 7781 (N = 165) and 8083 (N = 139) for limited disease; and 7782 (N = 151) for extensive disease. Besides ED (limited versus extensive), a four-point rating of PSR was obtained. Psychological distress was measured by the standardized Profile of Mood States (POMS). Gender, age, marital status, education, PSR, ED and two relevant interaction terms (PSR X ED; gender X ED) were analyzed using multiple linear and hierarchical regressions. Of the six main variables, gender and PSR had significant association with POMS total mood disturbance, a summary score for POMS emotional subscales, and most of the individual subscales. The PSR X ED interaction provided a rationale for testing a new regression model in which PSR and ED were combined into a single index of impairment. The final index resulted in five levels of physical impairment which bear an approximately linear relationship to increasing levels of distress (Overall regression, P less than 0.001). These data suggest that PSR is an important factor in modelling POMS distress at both levels of ED, and that ED becomes an important factor with poorer performance status only.
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PMID:The relationship of psychological distress, extent of disease, and performance status in patients with lung cancer. 362 Nov 36

The colony formation of human tumor xenografts from nude mice, of murine tumors, and of human bone marrow (CFU-C) has been investigated in vitro using a modification of the double-layer agar assay described by Hamburger and Salmon. Systematic modification of growth conditions and careful selection of viable tumor tissue enhanced the growth rate (at least 30 colonies per dish) of human tumor xenografts to 86% (98/114). The median plating efficiency was 0.07% which is comparable to the results observed by others using fresh human tumors. The growth of human bone marrow was stimulated with a placenta-conditioned medium, which allowed growth of granulocytic stem cell colonies (CFU-C). The median plating efficiency of the bone marrow was 0.08%. The murine tumors P388, L1210, B16 melanoma, Lewis lung carcinoma and colon carcinoma 38 grew very well in vitro. Excluding the Lewis lung carcinoma, the plating efficiency of these tumors was markedly higher than that of the human tumor xenografts and human bone marrow. The colony assay may have potential as a secondary screening system for identifying new active structures and also for indicating which tumor types are most responsive to a new antitumor agent. We test new structures in 20 well-selected human tumor xenografts and in the P388 mouse leukemia in dose-response relationships. The two most responsive xenograft tumors are subsequently studied in vivo in nude mice in order to determine if a new compound presents antitumor activity in an in vivo organism at a dose around the LD10 level. If a remission or at least no change is observed in the subcutaneously growing tumor, the new compound undergoes large disease-oriented testing usually in 60 xenografts. The in vivo studies are necessary in determining whether a compound has a more specific effect on tumor cells than on the dose-limiting normal tissue. The comparison of in vitro/in vivo activity allows an assessment of the relevant in vitro dose based on in vivo pharmacological behavior of a drug. It seems justifiable to apply the conclusions of this approach to the clinical setting because mouse toxicity data, e.g. the LD10, correspond well to the maximal tolerable doses in man. Moreover, for compounds whose dose-limiting toxicity is bone marrow suppression, the comparison of drug dosages effective in vitro on human bone marrow and tumor xenografts may prove helpful. The proposed testing strategy has been applied to TGU and Tiazofurin. At the relevant dosages TGU exhibited very limited activity in 67 human tumor xenografts studied.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Colony assay with human tumor xenografts, murine tumors and human bone marrow. Potential for anticancer drug development. 366 99

Prognostic factors were studied in 224 patients with small cell carcinoma of the lung entered in a Cancer and Leukemia Group B protocol. Extent of disease was the major predictor of complete remission (CR) frequency and survival greater than 2 years, with CR rates being 40% for patients with limited disease (LD) and 10% for those with extensive disease. Patients who were classified as having extensive disease on the basis of isotope scan evidence of a single bone metastasis had survival characteristics and response rates similar to those of patient with LD. A multivariate analysis of various factors, which may influence overall survival, reveals a good-risk population to be defined as having LD and an initial performance status less than or equal to 2, with or without a single metastatic focus on bone scan. Furthermore, this risk definition fairly successfully predicted which patients had the greatest chance of achieving a CR (45%). Age less than 70 years was shown to be a significantly adverse factor on survival in these multivariate analyses after adjusting for risk. When long-term survivors (less than 24 months) were investigated by multivariate analyses, the new risk system was found to be the only significant pretreatment factor. Interestingly, sex was the next marginally influential factor on long-term survival. Future stratification by these risk categories should lead to more homogeneous subgroups for comparison of different therapeutic approaches and should provide some indication as to how much better the newer treatment program is within each risk group.
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PMID:Prognostic factors in small cell carcinoma of the lung: a cancer and leukemia group B study. 626 94

4'-epi-doxorubicin (4'-epi-DX) is a new anthracycline antibiotic. It differs from doxorubicin (DX) by the epimerization of the OH group in position 4' of the aminosugar moiety, and was synthesized in an effort to find agents with a superior therapeutic index to the parent compound doxorubicin (DX). 4'-epi-doxorubicin binds to DNA and inhibits nucleic acid synthesis and function. The antitumor activity of 4'-epi-DX in several experimental tumors (Leukemias L 1210, P 388, Gross Leukemia, Sarcoma 180 ascitic and solid, C3H/HE mammary carcinoma) is similar to that of DX. However, 4'-epi-doxorubicin has greater antitumor activity than doxorubicin in Lewis lung carcinoma, MS-2 sarcoma lung metastasis, and human melanoma in athymic mice. In chronic toxicity studies there were no qualitative differences between 4'-epi-DX and DX; quantitatively, however, 4'-epi-DX was less toxic. In different experimental models 4'-epi-DX has been shown to be less cardiotoxic than its parent compound. In chronic toxicity studies in the rabbit, histopathologic findings revealed the same pattern of cardiotoxicity for both drugs but less marked with 4'-epi-DX. Distribution studies in mice with tumors showed a lower concentration of 4'-epi-DX in the heart, spleen and kidneys; the hepatobiliary metabolism and excretion of 4'-epi-DX investigated in the rat, indicated that the new analogue was more extensively metabolized than the parent compound. Pharmacokinetics of 4'-epi-DX in humans showed a multiexponential decrease of plasma levels; the same pattern was observed for the metabolite 13-OH epidoxorubicinol but with lower concentrations than the unchanged drug. A high plasma clearance (0.9-1.41/min), a terminal half-life of about 30-40 hr and a large volume of distribution were the main pharmacokinetic characteristics of 4'-epi-DX. A reduction of the dose appears to be appropriate in patients with liver function impairment. Phase II studies with 4'-epi-DX have indicated that the drug produces a pattern of acute toxicity, including acute cardiac toxicity, qualitatively similar to that of DX at identical doses but quantitatively lower, with particular regard to leukopenia and gastrointestinal toxicity. The range of single active doses is between 60 and 90 mg/m2, the most frequently employed doses schedules being 75 or 90 mg/m2 i.v. every 3 weeks. 4'-epi-DX has shown activity in a variety of tumors such as breast carcinoma, soft tissues sarcomas, NH lymphomas, leukemias, ovarian cancer and gastric cancer. Preliminary evidence of activity has been found in melanoma, rectal cancer and pancreatic cancer suggesting a broad spectrum of activity. As to chronic cardiac toxicity up to now only 2 mild to moderate and reversible CHF have been observed at doses of 1120 and 1235 mg/m2 in about 700 treated patients. Specific and comparative studies are in progress: preliminary findings from a randomized comparison of 4'-epi-DX vs DX in breast cancer indicated that 4'-epi-DX may have a lower cumulative cardiotoxicity.
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PMID:4'-epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. 634 72

Since the mid-1980s, the American Cooperative Cancer Treatment Groups (Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, North Central Cancer Treatment Group. Radiation Therapy Oncology Group, Southwest Oncology Group) have performed several multimodality trials exploring combinations of chemotherapy and radiation in patients with Stage III non-small cell lung cancer. The initial trials had a sequential design with induction chemotherapy followed by radiation. Later trials have emphasized concurrent chemoradiation with or without induction chemotherapy. These trials have begun to have an impact on what is considered 'standard' therapy for patients with Stage III non-small cell lung cancer (NSCLC).
Lung Cancer 1995 Apr
PMID:Multimodality therapy in unresected stage III non-small cell lung cancer: the American Cooperative Groups' Experience. 755 38


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