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

Recent clinical trials demonstrate the combined activity of 5-fluorouracil (5-FU) and interferon (IFN) in advanced colon cancer. Several possibilities exist for explaining the interaction. Interferon may alter the pharmacokinetics of 5-FU infusion by increasing the steady state concentration. Interferon enhances the inhibitory effects of 5-FU for tumor cells in culture. This enhancement is blocked by thymidine. Interferon reduces the concentration of thymidylate synthetase, and this may account for the thymidine-reversible interaction. An alternative mechanism invokes the immunomodulatory effects of IFN. Interferon augments the activity of killer cells with possible anti-tumor activity, both in vitro and in vivo. Also, by increasing the expression of human leukocyte class I antigens, IFN reduces the sensitivity of tumor cell lines to cell-mediated killing, an effect termed resistance. 5-Fluorouracil reverses the resistance in a time- and dose-dependent manner. The effect is mediated through inhibition of protein synthesis, since thymidine cannot reverse it. Fluorouridine is more active in reversing resistance than fluorodeoxyuridine. 5-Fluorouracil also reverses the induction of human leukocyte antigens by IFN. Studies in the resistance model suggest that high doses of 5-FU by infusion for several days might be the optimal method for modulation of IFN-induced effects.
 ...
PMID:Mechanisms of interaction of interferon and 5-fluorouracil in solid tumors. 171 44

Using the double agar layer method of human tumor clonogenic assay, the anticancer effect of different combinations of anticancer drugs and interferons was tested on 3 lung cancer cell lines, PC-13, PC-14, and Calu-1. The anticancer drugs and the concentrations used in this study were cisplatin (1.0 microgram/mL), adriamycin (1.0 microgram/mL), mitomycin C (0.2 microgram/mL), VP-16 (5.0 micrograms/mL) and 5-FU (5.0 micrograms/mL). Three kinds of interferon, alpha, beta and gamma in 5,000 units/mL, were tested in combination or in sequence with other anticancer drugs on lung cancer cell lines. The results demonstrate an enhanced anticancer effect on PC-14 only with sequential or simultaneous combination of VP-16 with alpha, beta and gamma interferons; and on Calu-1, only with sequential use of adriamycin and beta-interferon. Our results indicate that there is no unique way of combining anticancer drugs and interferons which can obtain an enhanced anticancer effect on all lung cancer cell lines. The best combination of interferon and anticancer drugs seems to be influenced by the biological characteristics of the cancer cells.
 ...
PMID:[Effect of combinations of anticancer drugs with interferons on human lung cancer cell lines evaluated by human tumor clonogenic assay]. 172 Jan 64

1. Pharmacodynamics and pharmacokinetics of antimetabolites. Antimetabolites are administered in the form of a base or its riboside, which is incorporated into the cell and converted to an active or inactive metabolite. The active metabolite remain in the cell inhibiting the enzymes to catalyze nucleotide synthesis for nucleotide triphosphate formation, but the inactive metabolites are rapidly excreted out of the cell. The inhibitory effect of antimetabolites on nucleotide formation is correlated with factors, such as maintenance of drug blood level, incorporation of the drug into the cell, activation and inactivation of the drug, affinity of the active form to the corresponding enzyme, and change in pool size of the intermediate metabolites in nucleotide synthesis. The salvage synthesis occurring at the higher level of the enzymes catalyzing nucleotide synthesis to counteract the inhibition by the drug is also correlated with the nucleotide formation. II. Pyrimidine antagonists 1. Cytosine arabinoside (ara-C) and its derivatives Ara-C is rapidly converted to ara-CTP and ara-U. The former remains in the cell and inhibits DNA polymerase, but the latter is excreted rapidly out of the cell. A small portion of ara-C is incorporated into DNA, which results in the degradation of DNA as demonstrated by reduced sedimentation of bulk DNA in alkaline sucrose gradient centrifugation and the ladder DNA fragmentation with a minimum fragment of approximately 180 base pairs and its conjugates in agarose gel electrophoresis. Behenoyl ara-C (BHAC) is highly lipophilic and highly distributed in the erythrocyte stroma and membrane fraction of leukocytes after iv infusion. The incorporated BHAC is released after the plasma BHAC level decreases, which suggests that erythrocytes can be a drug reservoir after iv infusion. Therefore, severe anemia should be treated before BHAC chemotherapy for longer maintenance of the plasma BHAC level. 2. 5-Fluorouracil (5-FU) and its derivatives Activation of 5-FU in the cells is metabolized by uracil metabolizing enzymes to FUMP and FdUMP. FUMP is further metabolized to FdUMP and is also incorporated to RNA. FdUMP produces a ternary complex with thymidylate synthetase and leucovorin; subsequently, conversion of dUMP to dTMP is strongly inhibited. Thus, FUMP and FdUMP inhibit RNA and DNA metabolism, respectively. Enzyme activity during 5-FU metabolism and consequently the degree of inhibition of DNA and RNA syntheses markedly differ with the tumor cell species. This should be taken into consideration when performing chemotherapy of malignancies.
 ...
PMID:[Clinical pharmacology of anticancer agents (Part 4). Antimetabolites (1)]. 173 42

Working with the antimetabolic chemopredictivity assay on short term cultures we evidenced a correlation between in vitro chemosensitivity of colorectal cancer and fractional incorporation of radionucleotides. Four different drugs (5-FU, mitomycin C, 4'-iododeoxydoxorubicin and ruboxyl, a nitroxyl derivative of daunorubicin) were tested on 102 tumor cultures. The extent of 3H-TdR and 3H-UdR incorporation into DNA and RNA in the related control cultures was in relationship with the chemosensitivity of the tumor. Along with the labeling index this simple metabolic-kinetic trait may gain a role for the screening of tumor phenotypes sensitive to chemotherapy.
 ...
PMID:Fractional incorporation of radionucleotides, a marker of in vitro tumor cell chemosensitivity in colorectal cancer. 174 92

To assess the feasibility and effectiveness of combined therapy on locally advanced cervical cancer, we entered 38 patients into a study. The patients were treated with mitomycin-C (10 mg/m2) on Days 1 and 30 and 5-FU (1000 mg/m2) on Days 1 to 4 and Days 30 to 33. In 5 weeks 4500-5000 cGy was given concurrently, followed by radioactive implants. Twenty-six patients had an early-stage disease (IB-IIB) and twelve had a late-stage disease (IIIB-IVA). Eighty-seven percent (33/38) of the patients had a tumor measuring 5 cm or more. The other 5 patients with a tumor size under 5 cm had biopsy-proven positive pelvic nodes; 2 of these 5 patients had a pretherapy hysterectomy. Tumor response, complete (CR) vs partial (PR), was assessed in 36 patients 3 months after completion of therapy. A CR was noted in 80% (29/36) of the patients. The PR status conferred a detrimental effect on the pelvic disease control (PDC), disease-free survival (DFS), and survival (S) while late stage correlated with the development of distant metastases (DM) and a poor DFS. PDC was obtained in 93% (27/29) of the patients who had a CR, as compared to only 43% (3/7) of those with a PR (P = 0.0228). The DFS and S rates were 59 and 77% for patients with a CR and 21 and 19% for those with a PR; respective P values were 0.0340 and 0.0002. Eleven percent (3/26) of the patients with an early stage developed DM, as compared to 50% (6/12) of those with late stage, (P = 0.0016). The DFS rates were 80 and 37% for patients with an early and late stage, respectively (P = 0.0141). Four patients developed transient neutropenia and one had transient thrombocytopenia. The second dose of mitomycin-C was omitted in 4 patients due to persistent neutropenia in 3 and to transfusion-related hepatitis in 1. Two percent (5/21) of the patients who had a staging laparotomy developed wound dehiscence. Three patients developed non-cancer-related small bowel obstruction requiring surgery. We concluded that this combined regimen was well tolerated. Although it was effective in controlling the cancer in the pelvis, this regimen failed to control DM in late-stage patients.
 ...
PMID:Mitomycin-C/5-FU and radiation therapy for locally advanced uterine cervical cancer. 175 91

A human colon cancer cell line Hce-8693 was heterotransplanted in nude mice. polyamine biosynthesis inhibitor alpha-difluoromethylornithine (DFMO) showed a marked reproducible inhibition in this model. The size and weight of transplanted tumor in DFMO group were smaller than those of the control group and the average inhibition rate was 72.8% (P less than 0.001). DFMO showed higher tumor inhibitory rate than 5-Fu (35.4%) (P less than 0.001). Furthermore, DFMO demonstrated less severe bone marrow inhibition in the nude mice than 5-Fu (20.0% vs 53.2%, P less than 0.001). There was no synergistic action in these two drugs at the experimental doses. The concentration of putrescine and spermidine in the serum and tumor tissue in the DFMO group were 70% lower than those of the control group (P less than 0.001). These results indicate that the anti-tumor effect of DFMO might be explained by the inhibition of polyamine biosynthesis and this study provides an experimental basis for future clinical application of DFMO.
 ...
PMID:[Inhibition by polyamine biosynthesis inhibitor DFMO of the growth of transplanted human colon cancer in nude mice]. 178 43

Treatment of RIF-1 solid tumors with 5-fluorouracil (5-FU, 100 or 200 mg/kg, ip) caused substantial regression of the tumors, with regrowth initiated on Day 6 (100 mg/kg) or Day 9 (200 mg/kg). Blood perfusion in the tumor, estimated by uptake of 86Rb+, was significantly increased after treatment with 5-FU, while Rb+ uptake in normal tissues (skin, muscle) was unaffected. The increase in tumor perfusion during the first few days following treatment was significantly greater in animals treated with the higher dose of 5-FU. Perfusion-dependent 86Rb+ uptake returned to control levels by the 9th day after treatment with 100 mg/kg of 5-FU, but remained elevated on Days 9-12 after the higher dose. By the 1st day following treatment with 5-FU, in vivo 31P NMR spectra of treated tumors indicated significantly higher ratios of phosphocreatine to Pi, higher pH, and lower ratios of Pi to nucleoside triphosphates compared to untreated age-matched controls. These changes persisted for 9 days following the lower 5-FU dose and for at least 12 days following the higher dose. Treatment with 5-FU induces profound, dose-dependent changes in tumor bioenergetics, which may result, at least in part, from changes in tumor perfusion after cytoreduction.
 ...
PMID:Tumor bioenergetics and blood flow in RIF-1 murine tumors treated with 5-fluorouracil. 179 94

More than 50% of the patients with large bowel cancer develop disseminated disease and invariably succumb. Adjuvant chemotherapy with 5-FU and levamisole have been shown to be more efficient than 5-FU alone or in combination with cytostatics. The combination of 5-FU, leukovorin and methotrexate induces prolonged survival with a good quality of life in metastatic colorectal cancer (CRC). During the last decade tumor immunotherapy has been an alternative facilitated by isolation and large scale production of cytokines and monoclonal antibodies. The mouse monoclonal antibody (MAb) 17-1A recognizes a tumor-associated antigen (TAA), present in high concentrations on the surface of gastrointestinal tumor cells. Injections of MAb 17-1A in patients with metastatic CRC induced generation of anti-idiotypic (ab2) in 90% and anti-anti-idiotypic (ab3) antibodies in 47% of the treated patients. The development of ab3 correlated significantly with survival (mean 80 weeks) while ab3- patients survive only 38 weeks. One of 52 patients treated with MAb 17-1A is a complete remission after 66 months, 3 had minor regression and 6 had a stable disease (19% RR). Based on in vitro findings showing increased antibody-dependent cellular cytotoxicity (ADCC) by the combination of granulocyte-macrophage colony stimulating factor (GM-CSF) and MAb 17-1A, 16 CRC patients have been treated with subcutaneously injections of GM-CSF for 10 days and intravenous infusions of MAb 17-1A at day 3. Two of 16 are in CR, 1 in MR and 3 in SD (37.5% RR). Minor side-effects were registered. A further development of immunotherapy of CRC might imply vaccination by injection of specific human anti-idiotypic antibodies (ab2) which mimics the nominal antigen, in order to induce a specific immunity.
Med Oncol Tumor Pharmacother 1991
PMID:Chemotherapy and immunotherapy of colorectal cancer. 180 82

A statistic analysis of 372 patients with maxillary sinus carcinoma treated between 1972 and 1983 was undertaken. One hundred eight patients were treated with the combined method consisting of 50 Gy irradiation, 2,000 mg 5-FU intraarterial infusion and tumor reduction surgery, the so-called extensive Denker's operation. Two hundred twenty-two patients were treated with the combined method not including extensive Denker's operation, and the other 42 patients with radiotherapy alone. The 5-year survival of these three groups were 48, 43, and 17%, respectively. The cumulative local control of the two groups with and without extensive Denker's operation was 51 and 33%, respectively. Maxillectomy as the second treatment was performed in 24 cases (22%) and 71 cases (32%) of the two groups of the combined method with and without extensive Denker's operation, respectively. On the other hand, 5-year survivors without maxillectomy of the two groups were 41 cases (38%) and 54 cases (24%), respectively. It was concluded that extensive Denker's operation plays an important role to increase the success rate of the initial treatment, decrease the rate of maxillectomy and increase the survival rate although it has a certain limit for the indication.
 ...
PMID:Combined therapy for maxillary sinus carcinoma with special reference to extensive Denker's operation. 182 Jul 45

The usefulness of 5'-DFUR in both patients with uterine cervical and ovarian cancers was investigated by determining pyrimidine nucleoside phosphorylase (PyNPase) activities and 5-FU levels in cancerous and normal tissues resected from them after oral administration of 5'-DFUR. In uterine cervical cancer, each group of 9 cases administered single dose of 400 mg of 5'-DFUR and 7 cases administered 400 mg of 5'-DFUR 3 times a day continuously for 7 days was investigated. In ovarian cancer, all of 9 cases were administered 400 mg of 5'-DFUR 3 times a day continuously for 7 days. In conclusion, PyNPase activities in the tissues of uterine cervical and ovarian cancers were higher than those in the normal tissues. 5-FU tissue levels in the cancerous tissues were significantly higher than in the normal tissues and blood as well. This tendency was observed in each of the single and continuous administration groups. These results suggest that the tumor selectivity which is one of characteristics of 5'-DFUR could be expected also for cancer in the field of gynecology.
 ...
PMID:[Investigation of 5-fluorouracil (5-FU) levels and pyrimidine nucleoside phosphorylase activities in the tissues from patients with uterine cervical and ovarian cancers after oral administration of 5'-DFUR]. 183 28


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