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)

Methotrexat (250-1100 mg/m2) was administered to 38 patients with malignant tumors by infusion of either 6 hours or of 75 minutes duration. MTX-infusion and continued at 3-6 hours interval for Citrovorum factor rescue was started 2 hours after 24 to 72 hours. 7 different MTX doses and rescue schedules were tested. It could be shown that MTX in the dose range used is effective in various tumors when CF-rescue is not higher than 7% of the administered MTX-dose, only occasionally therapeutic success was observed with higher doses. In the group of patients where CF-rescue was lower than 7% of the MTX dose on 9/14 patients objective tumor-regressions could be achieved. Conclusions drawn are discussed and the necessity of further investigations is emphasized.
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PMID:[Therapy of solid tumors using high-dose methotrexate and citrovorum factor]. 30 Aug 63

Multiple-dose toxicity of the 5-arylpyrimidine DDMP showed marked seasonal variation and sex dependence in BD2F1 mice. Considerable therapeutic activity against the ascitic, solid, and intracranial forms of Sarcoma 180 was demonstrated. Antitumor effects were highly schedule and dose dependent at a limited number of doses between 16 and 40 mg/kg. Antitumor activity (increase in lifespan) was approximately twofold greater against the ascitic tumor compared to the intracranial tumor at each dose level. The use of citrovorum factor rescue appeared to improve the therapeutic index of DDMP against intracranial Sarcoma 180 on specific multiple-dose schedules. Citrovorum factor rescue did not result in a greater initial antitumor effect of DDMP against the solid Sarcoma 180, but the effect was maintained for a longer period of time by allowing an increase in the number of doses which could be administered without toxicity.
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PMID:Experimental chemotherapy with 5-arylpyrimidine antifolates: Further studies on toxicity and the responsiveness of ascitic, solid, and intracranial sarcoma 180 to DDMP and DDMP with citrovorum factor. 30 37

High doses of methotrexate (HDMTX), given in pulse infusions of 3 to 30 mg/kg body weight, were studied in 22 children with non-Hodgkin's lymphoma. Sixteen complete and five partial remissions were observed in 21 patients evaluable for remission induction. The dose of MTX was increased stepwise on consecutive treatments until objective tumor response occured. Citrovorum factor rescue (CFR) was used "on demand" when toxicity started to develop, and routinely after 30 mg/kg of MTX. Twelve patients who had no previous chemotherapy were entered in a Phase II study consisting of remission induction with HDMTX and remission maintenance with monthly HDMTX supplemented with one monthly injection of vincristine and Cytoxan and five days of oral 6-mercaptopurine and prednisone. Eleven patients achieved remissions (eight complete and three partial) with HDMTX and one with surgery and radiation followed by HDMTX. The three partial remissions improved to complete remission during remission maintenance. All 12 were given the maintenance cyclic combination chemotherapy. Seven of the 12 patients entered the unmaintained phase of the study. One patient relapsed 6 months after cessation of therapy and died 4 years after diagnosis. Six patients are alive and free of disease 2 1/2 to 5 1/2 years after discountinuing treatment and 4 1/2 to 8 1/3 years after diagnosis. Five of these six patients had advanced (Stage IV) disease.
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PMID:Methotrexate and citrovorum factor rescue in the management of childhood lymphosarcoma and reticulum cell sarcoma (non-Hodgkin's lymphomas): parolonged unmaintained remissions. 78 84

From September 1989 until March 1992 nine patients with unresectable, though localized carcinoma of the pancreas were treated by a multimodality therapy consisting of palliative surgery, interstitial conformal brachytherapy in high-dose rate mode (HDRBT) with iridium-192 up to 30 Gy and external-beam radiation therapy (EBRT) of about 52 Gy. Four patients simultaneously received two cycles of chemotherapy consisting of 5-FU and Leucovorin. Since high radiation doses are applied which are not tolerated in adjacent healthy tissues, doses to tumor and critical areas need to be known precisely and are to be adjusted before treatment. A three-dimensional imaging system is required. A self developed method combines the data of simulation radiographs and those of CT scans. The prescribed minimum target absorbed dose in HDRBT is adjusted to the target volume sparing organs at risk. The specialized quality assurance is adapted to this method. Differences between measured and calculated doses do not exceed 5%. The addition of isodoses of HDRBT and EBRT on CT scans is demonstrated. Due to patients' selection the treatment concept did not reveal any positive effects on survival. However, excellent palliative results were obtained without severe side-effects.
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PMID:Combined isodose curves of high-dose rate interstitial brachytherapy with external-beam radiation therapy in pancreatic carcinoma. 138 54

We evaluated the efficacy of folinic acid (Leucovorin, LV) on cell lethality induced by 5-fluorouracil (FU) alone or in combination with cisplatin (DDP) by using the HEp-2 laryngeal squamous carcinoma multicellular tumor spheroids (MTS) system. For LV, non-toxic concentration of 10(-5) M was used. For cells in the monolayer, 6 and 24 h exposure to LV increased FU-induced cell lethality approximately 7- and 2-fold, respectively, whereas LV did not influence the effect of FU for MTS. LV's lack of effect on cells in MTS may be interpreted to mean that LV cannot penetrate the MTS. For the monolayer, simultaneous exposure to 3 drugs, DDP, FU and LV, produced synergistic interaction. However, sequential exposures were marginally synergistic or antagonistic, irrespective of sequence of DDP first or last. In contrast, DDP followed by FU plus LV was most synergistic for MTS. Simultaneous exposure was also synergistic, however, FU plus LV followed by DDP was antagonistic. These results suggest that LV is unable to penetrate into the MTS core to potentiate FU activity. DDP appears to have enhanced LV penetration into the MTS core. The exploration of means to overcome limited penetration of LV appears important for successful treatment of head and neck carcinoma.
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PMID:Effects of folinic acid on 5-fluorouracil induced cell lethality with or without cisplatin against head and neck laryngeal squamous carcinoma multicellular tumor spheroids. 144 99

Folinic acid (leucovorin, [LV]) can potentiate the growth inhibitory effects of fluorouracil (5-FU) in vitro and in vivo. LV is a precursor for 5,10-methylene-tetrahydrofolate (CH2-THF). Sufficient levels of CH2-THF enhance the inhibition of the enzyme thymidylate synthase by the 5-FU metabolite FdUMP. This study describes the effects of 5-FU and LV in two murine (C26-10, C38-1) and two human (WiDr, HT-29) colon carcinoma cell lines and in two murine tumors (Colon 26 and Colon 38). In vitro, only C38-1 was more sensitive for the combination of LV/5-FU compared with 5-FU alone. This effect was not dose or schedule dependent. l-LV, a purified stereo-isomere of LV, is thought to be the biological active form. Tests with this compound in vitro did not show a better effect than the mixture of d- and l-LV. In vivo, dl-LV could potentiate 5-FU antitumor effect in two murine colon tumors (Colon 26, Colon 38). This effect was clearly schedule dependent. dl-LV administered 1 hour before and together with 5-FU was much better than only simultaneous or posttreatment, but there was no dose dependency, while like in vitro l-LV effect was comparable to dl-LV. TdR was used to study the role of TS inhibition in the growth inhibitory effect of 5-FU with and without LV. TdR can reverse growth inhibition caused by TS inhibition due to 5-FU. In vitro, a partial reversal of growth inhibition of 5-FU and 5-FU/LV was observed, but in vivo there was no reversal. In vivo, TdR combinations led to high toxicity. Measurements of TS amounts in cells and tumors showed that those of human origin had much lower TS than the murine. C38-1 and Colon 38 with low TS were more sensitive to 5-FU than Colon 26 with higher TS amounts. TS inhibition was studied in the two murine colon tumors at several time points after weekly 5-FU or LV and 5-FU administration. LV did not increase the extent or retention of TS inhibition due to 5-FU during the first week. After three courses of treatment a fourfold increase of TS levels was seen in Colon 26 after 5-FU therapy. This resulted in a less effective TS inhibition after this treatment. Tumors treated with 5-FU and LV also showed an increase of TS, but to a lower extent, while the effect on TS inhibition remained the same.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of folinic acid on fluorouracil activity and expression of thymidylate synthase. 153 71

Twenty-eight patients with refractory advanced malignancies were treated with a 24 hr infusion of 5-fluorouracil (5-FU), Leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable for the assessment of toxicity and anti-tumor activity. PALA was administered as intravenous bolus over 15 min at a fixed dose, 250 mg/m2 24 hr before the start of 5-FU and LV infusions. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 2600 mg/m2. LV was administered in a fixed dose of 500 mg/m2 concurrently with 5-FU over a 24-hr period. The course was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among dose-limiting toxic effects. Other toxicities observed were hand-foot syndrome, hair loss of scalp/eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. Maximum tolerated dose (MTD) of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated at 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose de-escalation, a majority of whom contained 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients had been previously treated. Eight patients achieved a partial response, all of whom were previously treated, except three patients. A complete response was observed in a patient with pancreatic carcinoma, previously untreated. Overall response rate for the patients who were treated at the 5-FU dose of 2100 mg/m2 or 2600 mg/m2 is 9 of 18 patients (50%).
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PMID:Phase I study of high dose 5-fluorouracil and high dose Leucovorin with low dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies. 173 89

Previous studies from this laboratory indicated that the cytotoxic effects of the fluoropyrimidines on mouse leukemic cells are substantially augmented by folinic acid but that these effects are underestimated in growth inhibition experiments. These results have now been extended to two human tumor cell lines, the WiDr colorectal and T-24 bladder carcinoma cells. In both cell lines, the presence of folinic acid in the medium substantially enhanced the cytotoxicity of a 72-h exposure to either 5-fluorouracil (FUra) or 5-fluoro-2'-deoxyuridine. Folinic acid concentration-response curves for enhancement of the cytotoxicity of FUra to WiDr cells were broad but indicated that response was not maximal until at least 10 microM. Likewise, increased length of exposure to 10 microM folinic acid continuously enhanced the cytotoxicity of a 72-h treatment with FUra, but substantial enhancement was observed even after a 2-h exposure to folinate, and there was a diminished increment of cytotoxicity after 24-h exposure to folinic acid. Surprisingly, folinic acid augmentation of the cytotoxicity of a brief exposure to FUra (4 h) was minimal but enhancement of FUra cytotoxicity became much more pronounced with intervals of exposure to FUra of greater than or equal to 24 h. If these results can be mimicked in vivo without undue host toxicity, our experiments suggest that a substantial improvement in the therapeutic activity of FUra plus folinate would result from prolonged exposure to both agents.
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PMID:Schedule-dependent enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folinic acid. 183 2

The establishment of reliable preclinical test is essential for the reasonable clinical trial. As a methodology for the screening of new active anticancer agents, disease oriented strategy using human tumor cell lines has been proposed in USA. The important questions in DOS are to determine the representative cell lines of specific cancer and it is also extremely important to decide the numbers of cell lines used for the screening. CPT-11, topoisomerase I inhibitor, developed in my country has been demonstrated to be active against lung cancer cell lines compared with mice tumors such as S-180 and P-388. However, no compound is demonstrated to be clinically active so far by this methodology. The criteria for the application of clinical trial are obscure and each drug company decides empirically by themselves. We have proposed to use PEI (predictive efficacy index) for the prediction of antitumor activity of new compounds. The clinical effect of new platinum analogue well correlated with this value. We have conducted phase II trial of 5-FU + LV against NSCLC without no prior chemotherapy. No responder was observed in the trial. Augmentive effect of leucovorin on the cytotoxicity of 5-FU and FdUrd was examined in vitro against NSCLC and colon cancer cell lines. Leucovorin stimulated the cytotoxicity of both drugs only against colon cancer cell lines. We tried to predict the response rate of new platinum derivative based on the data of bioassay of patient's serum administrated with platinum compounds. The predicted response rates of 254-S were 57-67% and 16-27% against SCLC and NSCLC, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Preclinical trials from the standpoint of clinical trials]. 185 17

Leucovorin potentiates the cytotoxicity of fluorouracil (5-FU) in experimental tumor systems and appears to enhance the effectiveness of 5-FU in patients with colon cancer. Twenty-two eligible patients (18 previously untreated) with advanced pancreatic adenocarcinoma were treated in a phase II trial of leucovorin 500 mg/m2/d for 6 days by continuous intravenous infusion with 5-FU 370 mg/m2/d by rapid intravenous injection on 5 consecutive days, beginning 24 hours after initiation of leucovorin infusion. Among the 20 assessable patients, there were no complete or partial regressions, although there was one minor response lasting 4 months. Three patients had stable disease for 5, 20, and 21 months, respectively. Median survival was 10 weeks. Toxicity was predominantly mucosal; stomatitis grade 2 or worse was seen in five patients, and diarrhea grade 2 or worse was seen in four. Hospitalization for toxicity was necessary in four previously untreated patients and three previously treated patients. The median WBC nadir was 4.6 (range, 1.4 to 9.6) x 10(3)/microL, and the median platelet nadir was 147.0 (range, 69.0 to 240.0) x 10(3)/microL. This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity. It should not be considered a standard treatment for patients with this disease.
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PMID:Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma. 187 24


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