Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to reduce the toxicities of cisplatin (DDP) and/or to improve antitumor efficacy, a large number of new platinum analogues have been synthesized. 1,1-Cyclobutanedicarboxylato(2-aminomethylpyrrolidine)platin um(II) (DWA2114R) is one of them. In this study, we characterized the action mechanism of DWA2114R flow-cytometrically in 3 human lung cancer cell lines by using bromodeoxyuridine (BrdUrd), rhodamine 123 (Rho) and Ki-67 antibody (Ab), and compared the results with those for DDP. We found that the actions of these 2 platinum analogues were characteristically different at the subcellular level. Our observations may be summarized as follows. a) Simultaneous exposure of cells to DDP and BrdUrd resulted in decreases in fluorescence intensity, i.e. in the amount of BrdUrd incorporated into single-stranded DNA. b) DDP appears to be approximately 20-fold more active than DWA2114R in producing cell cycle perturbation. c) In PC-6 small cell carcinoma cells, DDP induced decreases in S phase cells and accumulation of cells in the G2M phase, whereas in PC-10 squamous carcinoma and PC-3 adenocarcinoma cells DDP produced S phase cell accumulation. Weak but similar changes occurred with DWA2114R. d) The high Ki-67 antigen cell population was decreased by treatment with either DDP or DWA2114R, but DDP reduced the low Ki-67 antigen population more than DWA2114R. e) In PC-10 and PC-6 cells, DDP suppressed Rho incorporation into live mitochondria, whereas DWA2114R produced no change in Rho incorporation. PC-3 cells were not affected by either DDP or DWA2114R. It is likely that these differences reflect the biological activities of DDP and DWA2114R.
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PMID:Flow cytometric analyses of the characteristics of tumor cells treated with two platinum compounds: 1,1-cyclobutanedicarboxylato(2-aminomethylpyrrolidine)- platinum(II) and cisplatin. 148 36

Using a gel mobility shift assay, we have identified proteins, in the nuclear extracts of a human lung cancer cell line, that recognize cis-diamminedichloroplatinum(II) (cis-DDP, CDDP)-modified DNA. A 158-base-pair double-stranded DNA fragment, derived from pBR322 plasmid DNA, was modified by either CDDP, tetrachloro(dl-trans)-1,2-diaminocyclohexaneplatinum(IV) (tetraplatin) or trans-DDP (the stereoisomer of CDDP and clinically ineffective). These platinum drug-modified probes were incubated with nuclear extracts and analyzed by gel mobility shift assay. Proteins in the extracts selectively recognized the clinically active platinum-modified DNA fragment. No binding to the trans-DDP-modified DNA fragment was observed. These proteins may play a role in the cytotoxicity or in a DNA repair process.
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PMID:Detection of proteins that recognize platinum-modified DNA using gel mobility shift assay. 212 89

We examined the chemosensitivity of 57 primary lung cancer specimens to 9 antitumor drugs, using the succinate dehydrogenase inhibition (SDI) test. Average succinate dehydrogenase (SD) activity was reduced to less than 50% by cis-diaminedichloroplatinum (II) (DDP), cyclophosphamide (CPA), carboquone (CQ), mitomycin C (MMC) and adriamycin (ADM). The lung cancer cells were relatively resistant to pepleomycin (PEP), 5-fluorouracil (5 FU), vincristine (VCR) and vindesine (VDS). Small cell lung cancers, or early stage lung cancers, tended to be more sensitive to these antitumor drugs. However, differences in sensitivity with respect to either histology, staging or degree of differentiation were not statistically significant. Correlation of SD activity between 2 drugs was high among those which inhibit DNA synthesis (DDP, CPA, CQ or MMC), or between VCR and VDS (inhibitor of mitosis), however, the correlation between VDS and CPA, CQ or DDP was weak. The SDI test is a simple in vitro method readily available to aid in selecting drugs to treat patients with lung cancer.
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PMID:Chemosensitivity testing of human lung cancer tissues using the succinate dehydrogenase inhibition test. 238 98

We compared cisplatin (cis-DDP) and two of its analogues, carboplatin (JM8, CBDCA) and iproplatin (JM9, CHIP) for their ability to retard the growth of multicellular tumour spheroids. The spheroids were derived from two human tumours, a neuroblastoma and a non-small-cell lung cancer. To produce a given level of regrowth delay in lung cancer spheroids, carboplatin and iproplatin were required at concentrations approximately 10 times that of cis-DDP. In the neuroblastoma spheroid experiments, iproplatin and cis-DDP produced the same level of regrowth delay when iproplatin was present at a concentration greater than 10 times that of cis-DDP. Carboplatin also required much higher concentrations than cis-DDP to produce equivalent regrowth delay in neuroblastoma. The dose-response curve produced by carboplatin on neuroblastoma spheroids displayed a pronounced shoulder in the low-dose region; this phenomenon was not seen with cis-DDP. These findings may have implications for the clinical use of these drugs and in particular would support a role for carboplatin in the treatment of lung cancer, since total free-drug exposure of patients to carboplatin may be up to 16-fold greater than with cis-DDP. However, one must be cautious about generalizing on the basis of results from only two cell lines as well as applying in vitro data to clinical situations.
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PMID:The relative effectiveness of analogues of cisplatin in the experimental chemotherapy of human non-small-cell lung cancer and neuroblastoma grown as multicellular spheroids. 253 68

Advanced malignant tumors of certain histological types contain a hypoxic and necrotic core. Multicellular tumor spheroids (MTS) have the characteristics of chronically hypoxic cells in the center. We studied the effects of physiological oxygen environment on MTS growth and the cell lethality produced by doxorubicin (DXR) and cisplatin (DDP). MTS were made from 2 human lung cancer cell lines; PC-6 small cell and PC-10 squamous cell carcinoma, and grown for 2, 3 or 4 weeks; either in 5% CO2/air or 5% 02/5% CO2/90% N2. They were exposed to graded concentrations of DXR for 1 hr and cell lethality was determined by clonogenic assay. In the physiological oxygen environment MTS growth was retarded for both cell lines. PC-6 MTS grown in physiological oxygen environment were more sensitive to DXR than those developed in air. The differential sensitivity was most pronounced with the 2 week old MTS and gradually narrowed with increasing MTS size. In contrast, PC-10 MTS developed in the physiological oxygen environment were more resistant to DXR than those in air; the differences were again most pronounced in 2 week old MTS. There were little differences in cell kill effects of DDP, irrespective of cells being in monolayer or in MTS and growing in air or in physiological oxygen environment. These observations are consistent with the interpretation that cells in PC-6 MTS are scarcely affected by the physiological oxygen environment but easily affected by DXR, whereas cells in PC-10 MTS responded vice versa.
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PMID:Effects of physiological oxygen environment on drug-induced cell lethality of multicellular tumor spheroids from human lung cancer. 275 45

We tested the sensitivity to doxorubicin (DXR) and cisplatin (DDP) of multicellular tumor spheroids (MTS) developed from 2 human lung cancer cell lines; PC-10 squamous cell carcinoma and PC-6 small cell carcinoma. DDP was able to maintain its efficacy in MTS: PC-10 MTS were only 3-fold more resistant to DDP than in monolayer and in PC-6 cells DDP induced cell lethality was essentially unchanged irrespective of cells being in a monolayer or MTS. Atomic absorption spectrometry revealed that DDP uptake was essentially identical, irrespective of cells being in monolayer or MTS. DDP's efficient cell kill effects in MTS seems to be explained by its good penetration into the MTS core. In contrast to DDP, these 2 types of cells responded differently to DXR. Thus, PC-10 MTS became progressively more resistant to DXR when their size increased, whereas the susceptibility of PC-6 MTS tended to increase when the MTS grew larger. Fluorescent microscopic study revealed that prominent DXR fluorescence was observed only at the outer layer of PC-10 MTS. In PC-6 MTS, however, DXR fluorescence was diffusely seen in the entire MTS at low concentrations; nevertheless, owing to PC-6 cells' high sensitivity DXR was able to exert cell lethality. The differences in distribution of DXR fluorescence between PC-10 and PC-6 MTS were corroborated by flow cytometric analysis.
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PMID:Effects of doxorubicin and cisplatin on multicellular tumor spheroids from human lung cancer. 345 48

In previous work the authors observed that platinum (free and bound) does not seem to accumulate in the peripheral compartment following the administration of two courses of cisplatin (cis-DDP) therapy (65 mg/m2) in patients with mammary and ovarian cancer. The aim of the present work was to study the disposition of platinum (Pt) after a higher dose of cis-DDP, to verify the rate of free drug penetration into the tissue and to observe changes in protein binding relative to the dose. cis-DDP, at the dose of 100 mg/m2, was administered i.v. over 60 min to patients with lung cancer. Serum and urine were collected before infusion and at various intervals afterwards. The plasma and urine levels of Pt were determined by flameless atomic absorption spectrophotometry, using a Varian model AAS 1475-GTA 95. Serum levels were analysed by a two-compartment open pharmacokinetic model. After the higher dose there was a substantial increase in central volume Pt and slight increase in peripheral volume Pt as compared with levels observed previously at the lower dose. In some subjects receiving high doses elimination half-life decreased and total body clearance increased, while in others these kinetic parameters were unchanged in comparison with those observed after a low dose. Protein binding seems to influence the persistence of platinum in the vascular space, modifying to a minor degree tissue penetration of the drug.
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PMID:Kinetics of platinum in cancer patients treated with cisplatin at different doses. 365 26

The present status of extracorporeally induced total-body hyperthermia (TBHT) for far-advanced cancer was presented from data collected from Japanese patients given this treatment. TBHT was most effective in lung cancer. In analyzing the anticancer effects of TBHT according to cancer site, the highest efficacy was observed in patients with their main cancer in the lung or liver, irrespective of whether tumorigenesis was primary or secondary. The anticancer effects were more enhanced when TBHT was combined with dosage of cis-DDP. What is important in combined chemotherapy is to determine what agent(s) should be applied and when. The most useful method for examining the thermosensitivity and thermochemosensitivity of agents for drug selection was the human tumor stem cell assay using individual cancer cells. Further, the usefulness of angiotensin II-induced hypertensive chemotherapy during TBHT in augmenting selective drug delivery to tumors was stressed.
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PMID:[Total-body hyperthermia and combined anticancer chemotherapy]. 393 33

Seventy-three evaluable patients with advanced measurable solid tumors were given cisdichlorodiammineplatinum (II) (DDP) at a dose of 20 mg/M2 IV for 1-5 days every 3 weeks, and 19 patients who failed on this low dose DDP protocol received a single high dose of 100 mg/M2 IV once every 3 weeks. Forty-six patients had received prior chemotherapy, and 29 patients were untreated. Results included four complete responses (5.5%) in malignant melanoma, spindle-cell sarcoma, adrenal carcinoma, and bladder carcinoma lasting 2 to 4 months. In 21 patients (28.8%), partial responses were achieved. Twenty-two patients (30.1%) showed stable disease and 26 (35.6%) had tumor progression. A response rate of 25% (4/16 patients) was found for malignant melanoma, 45.5% (5/11) for nonsmall-cell lung cancer, and 35.3% (6/17) for sarcomas of various types. One patient with teratocarcinoma, who relapsed on low-dose DDP, had another partial remission for 4 months after high-dose therapy. Toxicity was most commonly seen with gastrointestinal side effects and myelosuppression. Cumulative nephrotoxicity was prevented by prehydration and/or treatment with furosemide or mannitol.
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PMID:Phase II evaluation of fractionated low and single high dose cisplatin in various tumors. 653

The aim of this study was to examine antitumorigenic Cis DDP properties in metastatic brain tumors. Thirty-four untreated patients with brain metastases recorded by CAT scans or radionuclide scans plus neurological examinations underwent the treatment. Pathohistology of primary tumors mainly showed breast [8] and lung [8] carcinomas and melanomas [10]. Other localizations of primary tumors were infrequent. Cis DDP was administered in doses of 30 mg/m2 body surface daily over 4 days. All the patients received at least two cycles and 33 have been evaluated. No corticosteroids were administered concurrently. An objective response (seven complete and seven partial remissions) was observed in 14 out of 33 patients (42%). Six stable disease cases were also noted. A complete response (5-14 months) was observed in breast cancer [4], lung cancer [1], and melanoma [2]. Seven partial responses lasted 2-5 months. Antitumorigenic activity of Cis DDP was also noted in extracerebral tumor lesions, especially in breast cancer patients. Toxicity was moderate but tolerable. The results of this study have shown Cis DDP to possess antitumorigenic properties also in patients with metastatic brain tumors, a point that has not been proved so far.
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PMID:Phase II clinical trial of cis dichlorodiammine platinum (Cis DDP) in metastatic brain tumors. 676 44


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