Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evolving trends in the management of rectal cancer have focused on organ preservation, improved quality of life, and survival of patients. A significant shift is underway in our thinking about what constitutes the true rectum and defining the "proximal" and "distal" segments of the rectum. Tumor mobility remains a dominant prognostic factor in patient selection and choice of surgery. A clinical staging with tumor location in the rectum provides a logical algorithm for treatment decision making with either chemoradiation therapy or surgery as initial treatment of choice. Current rectal cancer management has largely focused on postoperative adjuvant radiation strategies with improvement reported for T3 and N+ cases. Recent data from Europe suggests that preoperative radiation has a significant advantage over surgery alone or postoperative treatment. This appears to be borne out by institutional studies of high-dose preoperative radiation (>45 Gy) in the United States. Aggressive preoperative combined chemoradiation has also led to significant downstaging of cancer with pathological complete response rates of 20% to 30%. This offers new options for surgical management of residual disease with endocavitary radiation or local excision. The development of new agents Gemcitabine, paclitaxel, and CPT-11 may also prove beneficial. New treatment strategies need to be coordinated with evolving knowledge of the biological behavior of the tumor based on its genetic fingerprints. c-Ki-ras and C-myc mutations have been implicated in tumor initiation and progression. A number of other tumor suppressor genes, APC gene, p53, and DCC have also been implicated in colorectal tumor carcigenesis. The modification of biological behavior by mutations in these genes is currently under study. This may guide new treatment strategies significantly reducing the death rates from rectal cancer and improving functional results of treatment.
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PMID:Critical issues in the evolving management of rectal cancer. 942 68

The uptake of [3H]formycin B by Ehrlich ascites tumor cells was examined in both normal Na+ buffer (physiological) and nominally Na+-free buffer (iso-osmotic replacement with Li+). These studies were conducted to further characterize the equilibrative nucleoside transporter subtypes of Ehrlich cells and to assess the contribution of Na+-dependent concentrative transport mechanisms to the cellular accumulation of nucleoside analogues by these cells. Formycin B is poorly metabolized by mammalian cells and, hence, can be used as a substrate to measure transport kinetics in energetically competent cells. Initial studies established that formycin B inhibited [3H]uridine uptake by the ei (equilibrative inhibitor-insensitive) and es (equilibrative inhibitor-sensitive) transporters of Ehrlich cells with Ki values of 48 +/- 28 and 277 +/- 25 microM, respectively. Similarly, [3H]formycin B had Km values of 111 +/- 52 and 635 +/- 147 microM for uptake by the ei and es transporters, respectively. When assays were conducted in the presence of Na+, plus 100 nM nitrobenzylthioinosine to prevent efflux via the es transporters, the intracellular concentration of [3H]formycin B exceeded the initial medium concentration by more than 3-fold, indicating the activity of a Na+-dependent transporter. Interestingly, the initial rate of uptake of [3H]formycin B was significantly higher in the Li+ buffer (es-mediated Vmax = 65 +/- 10 pmol/microliter . sec) than in the Na+ buffer (Vmax = 8.4 +/- 0.9 pmol/microliter . sec); this may reflect trans-acceleration of [3H]formycin B uptake by elevated intracellular adenosine levels resulting from the low Na+ environment. This model was then used to assess the interaction of gemcitabine (2',2'-difluorodeoxycytidine) with the equilibrative and concentrative nucleoside transporters. Gemcitabine, which has shown considerable potential for the treatment of solid tumors, was a relatively poor inhibitor of [3H]formycin B uptake via the equilibrative transporters (IC50 approximately 400 microM). In contrast, gemcitabine was a potent inhibitor of the Na+-dependent nucleoside transporter of Ehrlich cells (IC50 = 17 +/- 5 nM). These results suggest that the cellular expression/activity of Na+-dependent nucleoside transporters may be an important determinant in gemcitabine cytotoxicity and clinical efficacy.
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PMID:Interaction of 2',2'-difluorodeoxycytidine (gemcitabine) and formycin B with the Na+-dependent and -independent nucleoside transporters of Ehrlich ascites tumor cells. 973 97

Gemcitabine, 2'2'-difluoro-2'-deoxycytidine, is an inhibitor of DNA synthesis and has been shown previously in vitro and in vivo to enhance the cytotoxic activity of radiation as well as some chemotherapeutic agents. Because gemcitabine has shown clinical activity on its own in several solid tumors traditionally treated with radiotherapy, it was of interest to optimize the combination of gemcitabine and radiation. To determine the optimal gemcitabine dose to combine with irradiation and to determine the effect of gemcitabine on tumor growth, mice bearing SA-NH tumors were treated with 2.5 to 600 mg/kg gemcitabine, and subsequent tumor growth was determined. At low doses, gemcitabine induced transient growth delay, whereas higher doses showed both cytotoxic and cytostatic activity. Flow cytometric, histological, and mitotic analyses of irradiated tumors showed that gemcitabine induced a dose-dependent inhibition of DNA synthesis and induction of apoptosis of cells in S phase. DNA synthesis recovered in cells at the G1-S boundary of the cell cycle in a dose-dependent manner, and a parasynchronous movement of cells through the cell cycle ensued. To determine the optimal schedule for gemcitabine administration in relation to irradiation, tumor-bearing mice were given a single 50 mg/kg dose of gemcitabine at various times before or after irradiation. Gemcitabine enhanced radioresponse in a time-dependent fashion. The highest enhancement factors for tumor growth delay (1.68-2.03) were observed when gemcitabine was administered 24-60 h before irradiation. Although gemcitabine reduced the radiation tumor control dose at all administration times used, the greatest enhancement of tumor radiocurability occurred when gemcitabine was administered 24 h before irradiation (dose modification factor of 1.54). Moreover, gemcitabine decreased the lung metastatic rate in mice with local tumor control from 73% in mice receiving radiation alone to 40% in mice receiving the combination (all combination times included). These results suggest that gemcitabine has strong radioenhancing properties and that the greatest interaction occurs when gemcitabine administration precedes irradiation by 24-72 h. Preliminary studies indicate that normal tissues recover more quickly than tumor tissues from gemcitabine treatment; thus, optimized scheduling of gemcitabine and irradiation may serve to improve the therapeutic ratio of the combination.
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PMID:Enhancement of tumor radioresponse in vivo by gemcitabine. 989 94

The results of treatment of malignant pleural mesothelioma are quite unsatisfactory regardless of the substance or schedule employed. Although some activity is proved for anthracyclines, platinum compounds and alkylating substances, no chemotherapeutic regimen has emerged as a standard of care. Response rates documented in literature are between 10 and 20% for all these regimens. We report about a patient with locally advanced, unresectable pleural mesothelioma treated with the nucleoside analog gemcitabine (2,2-difluorodeoxycytidine). A 54-year-old male patient with unresectable pleural mesothelioma confirmed by thoracoscopic biopsy was treated with seven cycles of gemcitabine (1000 mg/m2 on day 1, 8 and 15) over a period of 36 weeks. Restaging by thoracic computed tomography (CT) scan was performed after 8, 20 and 36 weeks. At week 36 after beginning of treatment, the CT scan exhibited a substantial partial remission with a reduction of tumor volume of over 50%. The adverse effects of the therapy were very moderate with a hematotoxicity not exceeding WHO grade I and a mild 'flu-like syndrome' during the first three cycles which responded quite well to steroids. The compliance of the patient was excellent and his general condition improved significantly under therapy. Gemcitabine seems to be an active drug for the treatment of pleural mesothelioma. Compared to other active regimens it is normally very well tolerated by the patients. Because of these characteristics gemcitabine seems a suitable antineoplastic substance, especially in palliative settings. It would be worthwhile to test its activity in pleural mesotheliomas in controlled trials.
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PMID:Impressive remission in a patient with locally advanced malignant pleural mesothelioma treated with gemcitabine. 1019 45

Adenocarcinoma of the pancreas is the cause of 3-4% of cancer related deaths in Italy and over 80% of all patients exhibit advanced disease. Treatment with surgery and chemio-radiotherapy may have meaningful results in resectable and locoregional tumours respectively. Chemotherapy is the treatment of choice in metastatic disease as palliative intent, although pancreatic tumour is considered resistant to treatment with conventional cytotoxicity drugs. Assessment of response of primary tumor is extremely difficult because of its anatomical location and fibrotic reaction around the tumor. Furthermore, medical problems associated with the age of patients, reduced performance status (PS), mainourished conditions, jaundice and pain, limit patients' tolerance and response to chemotherapy. 5-fluorouracil (5-FU) is the most frequently used drug in the treatment of pancreatic cancer with a RR of 28% in the trials performed in mid 1980, while more recently studies have reported a RR of 5-15%. Biochemical modulation of 5-FU by leucovorin, PALA and interferon does not appear to produce better results than 5-FU alone. 5-FU-based combination chemotherapy (FAM, SMF, etc) have shown interesting results in phase II (30-40%), but in a randomized trial the results of combination were similar to 5-FU alone (< 15%). Also, regimens containing platinum gave disappointing results just as the other combinations and cannot be recommended outside prospective clinical trials. When chemotherapy was compared to best supportive care (BSC), the results demonstrated a survival gain. Six studies, comparing chemotherapy versus BSC and 3 trials showed statistically significant difference in survival for patients treated with chemotherapy. Recently, new drugs have been introduced in the treatment of gastrointestinal tumour (gemcitabine, CPT11, raltitrexed, taxanes, etc.). Gemcitabine is a novel nucleoside analogue that has shown a very favourable toxicity profile and RR of 10-15% in advanced pancreatic cancer. Data from a phase II and randomized comparative trials suggest that gemcitabine offers an advantage over 5-FU in terms of improvement of PS and general clinical symptoms. Given the difficulty of accurate tumor measurement in this disease, some authors introduced a novel new end-point to evaluate the response: clinical benefit (CB). In a randomized trial of gemcitabine vs. 5-FU, RR using CB was 23.8 with gemcitabine and 4.8 with 5-FU, this difference was statistically significant with a median survival of 5.6 and 4.4 months, respectively. In conclusion, future studies should focus on phase III trials with gemcitabine, alone or in combination and phase II with new promising drugs. Quality of life, pharmaco-economic studies, CB should be the principal end-point of these studies. All patients with advanced pancreatic cancer should be included in clinical cooperative trials.
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PMID:[Possibilities of palliation in pancreatic cancer]. 1023 81

Gemcitabine (2'2'-difluorodeoxycytidine, Gemzar) is a deoxycytidine analog with excellent antitumor activity against a number of solid tumors. Gemcitabine needs to be activated by deoxycytidine kinase and other kinases to its triphosphate, gemcitabine triphosphate, which can be incorporated into RNA and DNA. The latter effect is considered to be responsible for its antitumor effect and causes masked chain termination and inhibition of DNA repair. This effect may be of importance for combination with DNA interacting agents. In phase I trials daily, twice weekly, weekly and every two weeks schedules have been evaluated. At the weekly schedule of 1,000-1,250 mg/m&sup2; significant antitumor activity was observed in bladder, breast, ovary, and pancreatic cancer, non-small cell lung cancer (NSCLC), and small cell lung cancer of 31%, 33%, 22%, 11%, 22% and 27% total response rates, respectively. Gemcitabine also showed considerable improvement in clinical symptoms, while toxicity was not severe with mild myelosuppression. Due to its ability to inhibit DNA replication, combination studies were initiated with DNA damaging agents. For the various combinations with cisplatin in phase II studies on NSCLC, response rates varied from 42%-54%, with a median survival of generally more than 12 months. Also, combinations with taxanes, etoposide, doxorubicin and vindesin seem promising. Gemcitabine is an important agent for the management of several relatively chemoresistant cancer types, both with respect to anti-tumor activity and clinical benefit. Future research on combination studies deserves high priority considering the high response rates in NSCLC and bladder cancer.
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PMID:Gemcitabine: Future Prospects of Single-Agent and Combination Studies. 1038 42

Gemcitabine Hydrochloride (hereafter: Gemcitabine) is a new anti-tumor agent being widely used in other countries for treatment of non-small cell lung cancer was recently approved in Japan. The profile of Gemcitabine is considered to be the following 2 points both for non-small cell lung cancer and for pancreatic cancer, of which the study is currently conducted in Japan: high efficacy as foreign data indicate prolongation of survival time and less frequency of serious adverse reactions than other conventional anti-tumor agents. According to the results of Japanese and foreign phase I studies, as clinical pharmacological profile of Gemcitabine, its elimination half-life is rather short such as 20 minutes. Weekly administration by injection over 30 minutes is appropriate since bone marrow suppression and hepatic disorder were frequently observed in case of administration twice a week or injection for more than 60 minutes. Also, population pharmacokinetics results showed a tendency that blood plasma clearance of Gemcitabine was lower in women and aged patients. Dose adjustment depending on gender is not considered to be necessary because the blood plasma clearance amount of Gemcitabine is large enough itself. However, influence caused by aging must be observed continuously in the future. For its profile of mild adverse reactions of Gemcitabine mentioned above, concomitant chemotherapy with other anti-tumor agents is expected be widely conducted in the future, therefore, clinically pharmacological observation of Gemcitabine is important for its appropriate use as well.
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PMID:[Clinical development in gemcitabine and its clinical pharmacological profile]. 1039 13

Stimulated by surprising results in the first 7 patients treated with intraarterial/systemic chemotherapy with a combination of Mitomycin-C + Gemcitabine we now report on the data of 28 pancreatic cancer patients in comparison to 15 patients treated with gemcitabine alone(1000 mg/m2). Tumor response was evaluated on the basis of imaging methods, tumor markers and life quality parameters like body weight, pains and Karnofsky index etc. Tumor markers were monthly determined, imaging methods every 1-3 months. The locoregional/systemic approach included 3 week cycles with i.a. application of mitomycin-C + gemcitabine on day 1 and i.v. application of gemcitabine on days 8 and 15. The alltogether 125 cycles (mean 4 cycles per patient) resulted in 43% PR (n = 12), 1 CR (3%), 255 MR, 11% SD and 18% PD in the imaging methods and 20% CR, 60% PR, 4% MR and 12% SD in the course of the relevant tumor markers. Progression free survival amounted to a median of 7.5 (6) months defined by imaging methods (tumor markers). Second line treatments following new progress after effective locoregional approach with gemcitabine or a combination of gemcitabine + oxaliplatin did not result in a new tumor regression. However, third line therapy trials in 3 patients with high dose 5-FU or CPT 11 induced new antitumoral efficacy (survival of these tumors > 15, > 17 and > 28 months, n = 2 M1, n = 1 T3M0). About 75% of patients reported on a relevant benefit of life quality parameters. Side effects are on principle comparable to those of gemcitabine monotherapy, except for a tendency to a higher rate of pulmonary complications and 1 HUS observed. Even if not compared in a randomized study locoregional/systemic combined treatment modality seems to result in a higher rate of abjective tumor response defined by imaging methods as well as tumormarkers. Comparing tumor marker and imaging response to therapy CA 19-9 often showed a more rapid and subtle answer to therapy and an earlier new increase suggesting tumor markers as an essential part in the follow-up of these patients in order to optimize the patient's palliative treatment. Our results should stimulate the clinicians to rediscuss the chemosensitivity of exocrine pancreatic cancer and to perform prospective randomized studies focusing on combined gemcitabine approaches.
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PMID:Locoregional/systemic chemotherapy of locally advanced/metastasized pancreatic cancer with a combination of mitomycin-C and gemcitabine and simultaneous follow-up by imaging methods and tumor markers. 1047 Jan 75

Gemcitabine is a potent radiosensitizer in both laboratory studies and in the clinic. Initial laboratory studies showed that gemcitabine radiosensitizes a wide variety of rodent and human tumor cells in culture. Maximum radiosensitization occurs in cells that demonstrate concurrent redistribution into S phase and d-adenosine triphosphate pool depletion. Although the mechanism of sensitization is not yet clear, recent evidence from our laboratory suggests that gemcitabine lowers the threshold for radiation-induced apoptosis. Our preclinical data were used to design gemcitabine dose-escalation trials in combination with standard radiation for patients with unresectable head and neck cancer and pancreatic cancer. In head and neck cancer, we have found that gemcitabine doses far below the maximum tolerated dose for the drug when used alone significantly potentiate the toxicity of treatment. Comparatively, normal tissue sensitization has not been as marked in the treatment of pancreatic tumors. These findings have led us to conduct experiments using an animal model to improve the therapeutic index of treatment. We conclude that gemcitabine is a promising radiation sensitizer that will need to be developed cautiously if excessive normal tissue toxicity is to be avoided.
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PMID:Radiosensitization by gemcitabine. 1055 Aug 27

Gemcitabine is a novel antimetabolite which has shown anti-tumor activity against a variety of tumors including non-small-cell lung cancer (NSCLC). Phase I clinical trials with gemcitabine revealed it was well tolerated and several phase II trials were conducted. This report will summarize the data from 15 phase I-II trials conducted in both untreated and treated patients with advanced lung cancer. Overall, single-agent gemcitabine was active with response rates in untreated patients ranging from 14%-33% and 0%-25% in previously treated patients. Grade 4 toxicities were infrequent with neutropenia reported in 2%-6% of patients and grade 4 thrombocytopenia was rate (1%). One randomized phase III trial comparing the efficacy and safety of gemcitabine to best supportive care confirmed the role of gemcitabine as an active agent for the treatment of NSCLC. Furthermore, gemcitabine was shown in several economic models to be cost-effective. In summary single agent gemcitabine is active, minimally toxic, and cost-effective as a treatment regimen for patients with advanced lung cancer. Studies combining gemcitabine with other active agents are underway and have reported promising results. As monotherapy, gemcitabine may make a valuable contribution to those patients with a poor performance status or comorbid diseases desiring treatment studies in this setting should also be considered.
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PMID:The role of single-agent gemcitabine in the treatment of non-small-cell lung cancer. 1058 40


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