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

We have developed panels of human lung cancer cell lines with acquired and inherent resistance to cisplatin. Three parental cell lines, NCI-H69/P (small cell), COR-L23/P (large cell), and MOR/P (adenocarcinoma), were grown in increasing concentrations of cisplatin over a period of 6-9 months. This resulted in the development of sublines, H69/CPR, L23/CPR, and MOR/CPR which were 3- to 8-fold resistant to cisplatin as determined by a 6-day 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. None of the resistant sublines showed a significant change in cellular glutathione content or sensitivity to cadmium chloride (an indicator of metallothionein content), although changes in glutathione-S-transferase activity were seen. The sublines each showed cross-resistance to melphalan. Cisplatin accumulation was unchanged in H69/CPR, 1.3-fold reduced in L23/CPR, and 2.0-fold reduced in MOR/CPR compared with their respective parent lines. In a panel of 10 small cell lung cancer cell lines, there was a 16-fold range of sensitivities to cisplatin. The panels have been used to examine cross-resistance between cisplatin, carboplatin, iproplatin, tetraplatin, and a series of 10 novel ammine/amine dicarboxylate platinum(IV) compounds. Whereas H69/CPR and MOR/CPR showed little or no cross-resistance to any of the other compounds, L23/CPR was generally cross-resistant to all of them. In the panel of small cell lines, whereas the ranking of sensitivity to carboplatin and cisplatin were similar, each of the other compounds provided individual patterns of sensitivity. There was always a wide range of sensitivities among the panel, ranging from 8- to 28-fold. Among the dicarboxylate compounds, there was a great range of potencies, with two compounds (JM273 and JM274) being approximately 100-fold more potent than cisplatin.
 ...
PMID:Sensitivity to novel platinum compounds of panels of human lung cancer cell lines with acquired and inherent resistance to cisplatin. 132 13

Lung cancer is the most lethal cancer in the United States, with 143,000 deaths predicted for 1991. The cure rate is extremely low (approximately 13%), in part because the propensity for early spread precludes surgical cure in most patients. Thus, chemotherapy or other systemic therapies are the only way to improve the dismal results. Cisplatin is an active agent in small cell lung cancer (SCLC) and perhaps the most active agent in nonsmall cell lung cancer (NSCLC). The toxicities and inconvenience of cisplatin make it less than ideal for lung cancer therapy. Carboplatin was developed to provide a less toxic, more convenient alternative to cisplatin. The data presented in this review suggest that carboplatin may be substituted for cisplatin in the treatment of extensive-stage SCLC. In limited-stage SCLC, there are insufficient data to determine whether it should replace cisplatin when used simultaneously with chest irradiation and etoposide. It may be substituted for cisplatin in cycles not using irradiation. In NSCLC, carboplatin may be used alone or with etoposide for the palliative management of metastatic disease. Its role in earlier stages of NSCLC needs investigation.
 ...
PMID:Clinical experiences with carboplatin (paraplatin) in lung cancer. 132 16

Cisplatin lipiodol suspension (CLS: cisplatin 20 mg/ml) was percutaneously injected (cisplatin dose, 2, 4 or 6 mg/kg) in normal lungs of 10 rabbits (1.9-2.3 kg) to assess the safety and feasibility of intratumoral injection of CLS for lung cancer. Histological study revealed acute and chronic infiltrates with bronchiolitis and immature fibrosis at the injected lung tissue even at four weeks after injection. Intrathoracic leaks of CLS produced mild and focal fibrinous pleuritis. Intrabronchial leaks of CLS produced peripheral bronchiolitis with regenerative epithelia. However, no noxious parenchymal damage in the lung and surrounding tissues was noted. Neither oil embolism in brain nor renal toxicity was demonstrated. Seven of eight rabbits showed an increase in body weight. Concentration levels of plasma platinum were lower when compared with intravenous injection of cisplatin in the rabbit: highest at 30 minutes and unmeasurable one week after injection. Lipiodol accumulation in mediastinal lymph nodes was demonstrated in two of nine rabbits by X-ray examination, suggesting intralymphatic drainage of CLS. Intratumoral injection of CLS is safe even with CLS leaks in surrounding normal lung tissues and may be a potent therapy for controlling mediastinal lymph nodes metastasized from lung cancer as well as the primary tumor.
 ...
PMID:[Percutaneous injection of cisplatin lipiodol suspension (CLS) in rabbit lung, aiming at intratumoral injection therapy for lung cancer]. 133 70

Cisplatin (CDDP) is used widely in the treatment of a large number of carcinomas. The clinical use of cisplatin, however, can be complicated by myelotoxicity, intestinal toxicity and nephrotoxicity. We reviewed CDDP nephrotoxicity in 244 cases with primary lung cancer retrospectively. The enzyme histochemically localized in proximal tubular cells, N-acetyl-beta-D-glucosaminidase (NAG) and beta 2-microglobulin (BMG), a low molecular weight peptide normally reabsorbed by the renal tubular cells that has been used as an indicator for renal proximal tubular damage, were measured. And fractional excretion of Na (FENa%) and serum magnesium (Mg) levels were also measured before and after CDDP administration serially. The following results were obtained; 1) Over 45% of patients with lung cancer showed transient hyperexcretion of urinary NAG and BMG after CDDP administration. And peak excretion of NAG and BMG appeared to occur within 36 hours after administration of CDDP. 2) Almost all cases with persistent azotemia after CDDP administration showed high values of FENa (%), in spite of gradual normalization of urinary NAG and BMG excretion. 3) Hypomagnesemia was a common complication of CDDP nephrotoxicity that might be caused by a defect in renal Mg reabsorption. CDDP-induced nephrotoxicity seemed to be initiated by an acute, mainly proximal tubular impairment that reflects alterations in excretion of urinary enzymes and low molecular weight protein. In cases with persistent azotemia after CDDP administration depressed renal function might be attributed to the impairment of proximal as well as distal tubular reabsorptive functions.
 ...
PMID:[Clinical investigation of cis-platinum nephrotoxicity in 244 cases of primary lung cancer]. 147 19

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.
 ...
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

Preclinical data from studies of human lung cancer xenografts suggest that the cytotoxic effects of cisplatin are enhanced by alpha-interferon. To verify the above observations, the authors initiated a Phase II trial in advanced non-small cell lung cancer (NSCLC). Cisplatin was given at 100 mg/m2 during a 28-day cycle in a divided day 1 and day 8 schedule. Starting on day 1, alpha-2B interferon was administered intramuscularly at a dose of 5 million units three times a week continuously for a minimum of 2 months. Between January 1989 and September 1989, 30 patients were evaluated for response and toxicity. According to the staging system proposed by Mountain, 20 patients had Stage IV disease, 7 had Stage IIIB disease, and 3 had Stage IIIA disease. Expression of neuron-specific enolase (NSE) and Leu-7 was immunohistochemically investigated to evaluate possible relationship to treatment response. The response rate was 13.3% (95% confidence interval [CI]: 1.2% to 25%). The four responders showed positivity for NSE, and two of them were positive for Leu-7. An average of three cycles was given. The mean dose intensity administered was 83% of the projected dose for cisplatin and 92% of the projected dose for alpha-2B interferon. A standard scale was used to assess interferon toxicity. Hematologic, renal, and systemic side effects were not significant. In advanced NSCLC the addition of alpha-2B interferon did not increase the cisplatin-induced response rate. Further studies should be performed to determine the real value of chemotherapy response in tumors showing positive immunoreactivity for neural markers such as NSE and Leu-7.
 ...
PMID:A phase II study of days 1 and 8 cisplatin and recombinant alpha-2B interferon in advanced non-small cell lung cancer. 170 45

Cisplatin (CDDP), 5-fluorouracil (5-FU), and hydroxyurea (HU) have individually demonstrated activity against several solid tumors, act synergistically with each other in vitro, and may act as radiation sensitizers. Therefore, we designed a phase I study to determine the maximally tolerated dose of cisplatin as given in addition to our previously described combination of 5-FU, HU, and concomitant radiotherapy (XRT). Patients exhibiting advanced solid tumors requiring palliative XRT were eligible. The regimen consisted of 1 g HU given p.o.b.i.d. on days 1-5, 600 mg/m2 5-FU given i.v. daily by continuous infusion (c.i.) on days 1-5, escalating doses of cisplatin starting at 10 mg/m2 daily given by c.i. on days 1-5, and involved-field XRT carried out on days 1-5. The cycle was repeated every 14 days until the target XRT dose had been reached. In all, 19 patients were entered at the first dose level, and cumulative grade 3-4 myelosuppression was seen in 16 subjects. As no dose escalation was feasible, the chemotherapy was subsequently altered by using the above regimen for cycles 1, 3, 5, and 7 and substituting the less myelosuppressive regimen of 1 g HU given p.o.b.i.d. on days 1-5, 400 mg/m2 5-FU given i.v. daily by c.i., and 100 mg leucovorin given p.o.4 h on days 1-5 for cycles 2, 4, and 6. On this alternating program, 28 patients were treated with escalating doses of CDDP. The dose-limiting toxicity was again myelosuppression, which was prohibitive at a CDDP dose of 20 mg/m2 daily. In the final phase of the protocol, 30 subjects were treated with the above alternating-cycle regimen at a CDDP dose of 20 mg/m2 daily and a decreased HU dose of 500 mg p.o.b.i.d. in an attempt to circumvent the myelosuppression associated with this dose of CDDP. Although severe acute toxicity (cycles 1 and 2) was observed less frequently, cumulative toxicity (all cycles) remained pronounced. The other major toxicity encountered was mucositis, which was particularly pronounced in patients receiving radiation to the head and neck and following leucovorin-containing cycles. Plasma concentrations of free platinum did not correlate with the CDDP dose, possibly due to the narrow range of doses given. Pharmacodynamic modeling demonstrated that the CDDP dose and the HU dose were associated with leukopenia. Antitumor activity was demonstrated in a number of solid tumors particularly non-small-cell lung cancer and head and neck cancer.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:5-Fluorouracil, leucovorin, hydroxyurea, and escalating doses of continuous-infusion cisplatin with concomitant radiotherapy: a clinical and pharmacologic study. 173 49

The Lung Cancer Study Group conducted a phase II pilot study of concurrent chemotherapy and radiation therapy (chemoradiotherapy) before surgery in 85 eligible patients with non-small-cell cancer limited to the chest but in whom attempted resection would have been likely to leave residual disease (advanced stage IIIA and minimal stage IIIB disease). Cisplatin, 75 mg/m2, was given on days 1 and 29; fluorouracil, 1 g/m2 per 24 hours, was administered as a continuous infusion on days 1 through 4 and on days 29 through 32; and thoracic radiation, 30 Gy in 15 fractions, was administered on days 1 through 19. Two patients achieved a complete response and 46 patients had a partial response for an overall response rate of 56%. Toxicity from chemoradiotherapy was moderate but acceptable. Eight weeks after therapy was initiated, 54 patients underwent thoracotomy and tumor resection was attempted: 29 (34%) had complete resection and 15 (18%) had incomplete resection. Although surgical dissection was generally more difficult than in patients not pretreated with chemoradiotherapy, there was no apparent increase in postoperative complications. In 8 patients (9%), no viable tumor was detected pathologically in the resection specimen. Of the 18 patients whose tumors were completely resected and had disease recurrence, none had recurrence only in the chest, 12 (67%) had recurrence only in distant sites, and 3 developed second primary tumors. Median survival of all patients was 13 months. The overall results do not indicate a major benefit from this preoperative chemoradiotherapy regimen in patients with advanced but potentially resectable non-small-cell lung cancer. These results suggest a need to define better the relative roles of preoperative radiotherapy and chemotherapy.
 ...
PMID:Preoperative chemotherapy (cisplatin and fluorouracil) and radiation therapy in stage III non-small-cell lung cancer: a phase II study of the Lung Cancer Study Group. 184 20

Fifteen patients aged over 65 years of age with advanced non-small-cl lung cancer (mean age = 70.7, stage IIIb: IV = 4:11) were treated with combination chemotherapy consisting of Cisplatin (50 or 80 mg/m2) and a vinca-alkaloid (Vindesine 3 mg/m2 or Etoposide 80 mg/m2). The effectiveness and side effects of this cisplatin therapy in different combinations of vinca-alkaloid regimens (Vindesine vs Etoposide) were examined. The mean dose of Cisplatin in the Etoposide combination group (75.2 mg/m2) was significantly higher than that in the Vindesine combination group (54.3 mg/m2) (p less than 0.01). A notable reduction the tumor size was observed in 25% of the Etoposide group, only. The 6-month survival rate and one-year survival rate were respectively 85.7%, 57.1% in the Vindesine + Cisplatin group, and 87.5%, 50% in the Etoposide + Cisplatin group. The common side effects were nausea, vomiting, anorexia, and alopecia. These symptoms were either alleviated by antiemetic drugs or followed by spontaneous recovery. Leucopenia, anemia and thrombocytopenia were found in both groups, and there was no difference in the time course of myelosuppression between the two groups. The extent of nephrotoxicity was assessed by creatinine clearance rate. Its decrease in the Vindesine group (60.1----38.9 ml/min) was higher than that in the Etoposide group (64.9----48.9 ml/min), while there was no significant change in BUN, serum creatinine and urine NAG between the two groups. There were no cases in which chemotherapy schedules had to be interrupted due to myelosuppression and nephrotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Cisplatin and vinca alkaloid combination chemotherapy of advanced non-small-cell lung cancer in the aged]. 196 86

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.
 ...
PMID:Detection of proteins that recognize platinum-modified DNA using gel mobility shift assay. 212 89


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