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)

Chronic weekly administration of FUra to CD8F1 female mice bearing spontaneous mammary tumors produced body weight loss during the first 2 weeks of treatment, which became less severe during subsequent weeks of therapy. To our knowledge, the development of such a decrease in FUra toxicity in vivo during chronic treatment with the drug has not been described previously, and a study of this phenomenon was therefore undertaken in tumor-free CD8F1 female mice. Weekly administration of FUra at 85 mg/kg resulted in toxicity expressed in body weight loss and in depressed peripheral WBC levels; however, the magnitude of these toxic effects decreased significantly by the 5th week of treatment. Pretreatment of normal mice with FUra for 7 weeks resulted in a dose-related shift in the LD50 of FUra administered as a subsequent challenge. Compared with an LD50 of 240 mg/kg for FUra in normal mice, the LD50 in mice pretreated with FUra at 50 or 85 mg/kg per week was found to be significantly elevated to 370 and 460 mg/kg, respectively. Pretreatment with FUra at 85 mg/kg for 7 weeks did not alter the activity of the enzymes responsible for the activation of FUra, namely uridine kinase or orotate phosphoribosyltransferase, in the intestinal epithelium or bone marrow, but it did decrease the 24-h urinary excretion of intact [3H]FUra by almost 40% (P less than 0.01). In addition, the FUra pretreatment schedule resulted in a 31% (P = 0.14) increase in the activity of dihydrouracil dehydrogenase in the liver. These results suggest that increased degradation of FUra can be induced by chronic treatment with the drug. Finally, knowledge of the development of increased drug catabolism was used to increase the therapeutic effectiveness of FUra by its incorporation into an increasing-dose regimen. Mice bearing 24-h transplants of the murine breast tumor were treated with a constant dose of FUra for 12 weeks or with a dose that was increased, after 7 weeks, to a dose normally causing a high degree of drug-related mortality. The group receiving the incremented FUra dose had a significantly slower tumor growth rate without an increase in drug-related toxicity. These results are discussed in light of their obvious clinical implications.
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PMID:Decreased host toxicity in vivo during chronic treatment with 5-flourouracil. 396 61

At a nontoxic dose (50 microM), the two potent uridine phosphorylase inhibitors, benzylacyclouridine and benzyloxybenzylacyclouridine (BBAU), potentiated 5-fluoro-2'-deoxyuridine (FdUrd) growth inhibition of human pancreatic carcinoma (DAN) and, to a lesser extent, human lung carcinoma (LX-1) cells in culture. BBAU was more effective than benzylacyclouridine. BBAU (50 microM) enhanced the cytocidal effect of FdUrd (1 microM, 3 hr) on DAN grown on soft agar from 75 to 88%. In antithymocyte serum-immunosuppressed mice bearing DAN, the mean tumor weight in animals treated with FdUrd (50 mg/kg/day for 2 days) was 11% less than that of untreated controls. When BBAU (10 mg/kg/day for 2 days) was coadministered, the mean tumor weight at Day 10 was 78% less than untreated controls, with no apparent host toxicity, clearly demonstrating the potentiation of the antitumor effects of FdUrd by BBAU. The fact that DAN responded better than LX-1 to benzylacyclouridine and BBAU could be due, in part, to the lower relative activity of thymidine phosphorylase to uridine phosphorylase in DAN compared to LX-1. The activities of other enzymes involved in FdUrd metabolism, thymidine kinase, uridine kinase, orotate phosphoribosyltransferase, 5'-nucleotidase, and dihydrouracil dehydrogenase, did not differ between the two cell lines.
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PMID:Potentiation of 5-fluoro-2'-deoxyuridine antineoplastic activity by the uridine phosphorylase inhibitors benzylacyclouridine and benzyloxybenzylacyclouridine. 623 86

A patient with recurrent C-cell carcinoma of the thyroid is presented. Tumor masses and metastatic lymph nodes were detected by 99mTc-DPD on a preoperative bone scan. In contrast to other causes of extraosseous accumulation of bone-seeking phosphonates, the high affinity of amyloid is the main factor in the case of C-cell carcinoma. Because amyloid is the typical histochemical sign of the carcinoma type, imaging with phosphonates is expected to be another specific diagnostic procedure in addition to calcitonin measurements. The role of other markers in thyroid carcinomas is discussed.
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PMID:99mTc-phosphonates for imaging of amyloid in C-cell carcinoma. 662 40

Thirty-five patients with painful bone metastases arising from a variety of tumor types underwent a clinical trial in which 153Sm-EDTMP was injected as a single intravenous dose. The injection ranged in amount from 330 MBq to 1110 MBq of 153Sm-EDTMP. Pain relief usually occurred within one week after administration. The duration of pain relief lasted from 2 to 17 weeks. A detectable degree of pain palliation was experienced by 80% of the treated patients; 54% reported substantial or complete pain relief. Due to the small number of patients, no clear-cut dose-related response was detectable. Moderate myelosuppression was observed in one patient (WHO grade III). The metastatic lesion-to-normal bone ratios remained constant (varying from 1.5 to 4.8) for at least 5 days post-injection. 153Sm cleared very rapidly from the blood. Less than 1% of the injected dose remained in circulation at 4 hours post-injection. No local accumulation of the tracer could be detected outside the skeleton. Urinary excretion was quite complete at 6 hours post-injection. The biodistributions of 153Sm-EDTMP and 99mTc-DPD are very similar in metastatic and normal bone; thus, bone scanning can be used for patient selection and followup. According to our results, it seems that higher doses of 153Sm-EDTMP can be given safely and without any irreversible myelosuppression.
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PMID:Samarium-153-EDTMP in bone metastases. 754 88

Fluorouracil (FU) is essentially eliminated in the liver through the rate limiting enzyme dihydropyrimidine dehydrogenase (DPD). DPD is also expressed in various other normal as well as in tumor tissues. DPD activity measured in peripheral blood mononuclear cells (PBMC) is correlated to FU systemic clearance, but this correlation is weak, precluding PBMC-DPD to be considered as a reliable predictor of FU clearance. Nevertheless, patients with suspected or proven PBMC-DPD deficiency exhibit severe FU-related toxicities. Population studies performed so far were unable to detect complete DPD deficient patients, suggesting that complete DPD deficiency is a very rare event; however 3% of patients exhibit a partial DPD deficiency indicative of increased risk for developing FU-related toxicity. Although FU resistance is multifactorial, DPD activity in tumor cells (in vitro and clinical studies) is significantly related to FU sensitivity: the lower the DPD activity, the greater the FU efficacy. Further prospective clinical studies will be required in order to confirm the present observations.
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PMID:Dihydropyrimidine dehydrogenase (DPD) and clinical pharmacology of 5-fluorouracil (review). 782 62

5-Ethynyluracil (5-EU; 776C85) is a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase that improves the antitumor activity of 5-fluorouracil (5-FU) to a greater extent than can be accounted for by the improved 5-FU pharmacokinetics that result from preventing the catabolism of 5-FU. We therefore tested the effects of (R)-5-fluoro-5,6-dihydrouracil (5-FUH2), the 5-FU catabolite extensively formed in the absence of 5-EU, on the antitumor activity and toxicity of 5-FU in 5-EU-treated rats bearing large s.c. tumors. Rats were dosed once weekly for 3 weeks with the following regimens: 100 mg/kg 5-FU (maximum tolerated dose), 10 mg/kg 5-FU 1 h after 1 mg/kg 5-EU, or 10 mg/kg 5-FU plus 90 mg/kg 5-FUH2 1 h after 1 mg/kg 5-EU. The latter regimen was designed to approximate the exposure produced from 5-FU in the absence of 5-EU, where > 80% of the dose is catabolized. 5-FU produced complete and sustained tumor regressions in 94% of the animals pretreated with 5-EU. In contrast, 5-FU in combination with 5-FUH2 produced complete regression in only 38% of the 5-EU-treated rats, which was similar to the antitumor activity of 5-FU in the absence of 5-EU. All treatments resulted in 7-11% transient weight loss. 5-FU produced no other notable toxicity in 5-EU-treated rats. However, 5-FUH2 added to this regimen caused transient diarrhea and stomatitis in 13% of the animals, which was similar to the toxicity produced by 5-FU in the absence of 5-EU. Thus, 5-FUH2, or other downstream catabolites of 5-FU, impaired the antitumor activity and slightly increased the toxicity of 5-FU. Accordingly, 5-EU approved to improve the efficacy of 5-FU by preventing the formation of 5-FU catabolites.
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PMID:Attenuation of the antitumor activity of 5-fluorouracil by (R)-5-fluoro-5,6-dihydrouracil. 788 16

5-Benzyloxybenzyluracil (BBU) is the most potent inhibitor (Ki approximately 30 nM) of dihydrouracil dehydrogenase (EC 1.3.1.2), the first enzyme in the catabolic pathway of pyrimidine bases and their analogues, including 5-fluorouracil (FUra). The effect of BBU on modulating the chemotherapeutic efficacy and host toxicity of FUra was evaluated using human colon carcinoma DLD-1 grown in culture and as xenografts in anti-thymocyte serum (ATS)-immunosuppressed mice. The effect of BBU on FUra-induced host toxicity was also studied in nontumor-bearing-ATS-immunosuppressed and immunocompetent mice. At 0.2 microM, BBU potentiated growth inhibition by FUra of DLD-1 cells in culture (the concentration that produces 50% inhibition of cell growth was 0.48 microM at 3 h) by 1.3-fold (from 45 to 28% growth). BBU also enhanced the cytocidal effect of FUra (0.48 microM, 3 h) against DLD-1 grown in soft agar by 3-fold (from 45 to 15% growth). In ATS-immunosuppressed mice bearing DLD-1 xenografts, coadministration of BBU with FUra enhanced not only the efficacy of FUra in killing the tumor but also protected the host from FUra-induced host toxicity. This was particularly evident at low doses of FUra. Coadministration of BBU (10 mg/kg/day x 2) with FUra at 30 mg/kg/day x 2 reduced tumor weight by 16-fold (from 799 to 49 mg) and increased host survival from 83 to 100%. The enhancement of tumor kill and protection from host toxicity induced by FUra was also evident at higher doses of FUra, albeit to a lesser degree. At 120 mg/kg/day x 2 FUra, coadministration of BBU (10 mg/kg/day x 2) reduced tumor weight from 44 to 10 mg and increased survival of the animals from 33 to 50%. Host protection from FUra-induced toxicity was corroborated further by the protective effect of BBU, inferred from the increase in the dose that produces 50% mortality in ATS-immunosuppressed (from 135 to 195 mg/kg/day x 2) and immunocompetent (from 250 to 300 mg/kg/day x 2) mice. Therefore, coadministration of BBU improved the therapeutic index of FUra by 5.5-fold (from 2.3 to 12.6) as a result of potentiating the antitumor efficacy of FUra and reducing its induced host toxicity. This protection by BBU sharply contrasts with the effect of most other dihydrouracil dehydrogenase inhibitors, which at therapeutic doses increase host toxicity by FUra. These findings may lead to a more successful use of FUra in cancer chemotherapy.
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PMID:Potentiation of 5-fluorouracil efficacy by the dihydrouracil dehydrogenase inhibitor, 5-benzyloxybenzyluracil. 792 35

5FU tends to be used more and more frequently; this fact can be explained by its modulation, mainly by folinic acid. Pharmacokinetic follow-up of 5FU with dose adaptation has demonstrated its clinical usefulness by reducing significantly drug side-effects without any impairment in tumor response. Whatever the anticancer drug considered, it is theoretically possible to predict individual capacities for clearing it. This possibility has been explored for 5FU. Among the different tested variables only gender has a determined influence with females showing an average 15% reduction in 5FU clearance as compared to males. Age, hepatic function, nutritional status have no clear influence on 5FU clearance. 5FU catabolism is governed by a key enzymatic step involving dihydropyrimidine dehydrogenase (DPD). Recent case reports have shown that patients with partial or total DPD deficiency shown in lymphocytes were exhibiting severe 5FU related toxicities. A positive and significant correlation has been established between 5FU clearance and DPD activity measured in lymphocytes. This correlation is too weak for allowing individual 5FU dose to be calculated on the basis of lymphocyte DPD activity. Nevertheless DPD determination may allow high risk patients, with partial or total DPD deficiency to be identified.
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PMID:[Evolution from pharmacokinetics to pharmacogenetics. The example of 5-fluorouracil]. 805 51

5-Ethynyluracil (EU; 776C85) is a potent inactivator of dihydropyrimidine dehydrogenase, the enzyme that rapidly degrades 5-fluorouracil (FUra). We have investigated the antitumor activity and toxicity of FUra alone and in combination with EU in rats bearing advanced colon carcinoma. Two schedules were studied: (a) FUra daily for 4 days i.v. push (daily x 4); and (b) FUra administered i.v. push weekly for 3 weeks (weekly x 3). EU was administered at 1 mg/kg 1 h before FUra and for two additional days post-FUra therapy. The maximum tolerated doses of FUra alone were 35 and 100 mg/kg/day and for FUra plus EU were 10 and 15 mg/kg/day for the daily x 4 and weekly x 3 schedules, respectively. The dose-limiting toxicities were diarrhea and stomatitis both for FUra alone and for FUra in combination with EU. Although EU was not toxic and not active as an antitumor agent, it markedly improved the efficacy and therapeutic index of FUra. The antitumor activity of FUra was schedule dependent, yielding 13% complete and sustained tumor regression on the weekly schedule and no complete and sustained tumor regression on the daily schedule. The combination of FUra and EU produced 100% complete and sustained tumor regression on both schedules. The therapeutic index was < or = 1 for FUra alone and 6 for FUra with EU. EU was considerably more effective than either leucovorin or N-(phosphonacetyl)-L-aspartate as a modulator of FUra. Leucovorin or N-(phosphonacetyl)-L-aspartate induced minimum improvements on the daily schedule and only increased the therapeutic index to 1.5 on the weekly schedule. Because a 4-day continuous infusion of FUra alone at the maximum tolerated dose did not improve FUra therapy, we conclude that the improvements by EU involve additional modulations that complement the enhanced exposure of FUra.
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PMID:5-Ethynyluracil (776C85): modulation of 5-fluorouracil efficacy and therapeutic index in rats bearing advanced colorectal carcinoma. 813 56

3-Cyano-2,6-dihydroxypyridine (CNDP) was identified as a potent inhibitor (IC50 value, 4.4 nM) of dihydrouracil dehydrogenase (DHUDase) [EC 1.3.1.2], a rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. The inhibitory activity of CNDP was about 2,000 times that of uracil under our assay conditions. Kinetic analyses with partially purified enzyme from rat liver revealed that the mechanism of inhibition of DHUDase by CNDP was of mixed type with an inhibition constant (Ki) of 1.51 nM. CNDP had less effect on 5-FU phosphorylation than on 5-FU degradation. The inhibitory effect of CNDP on ribosylation of 5-FU was 600 to 1,000 times less than that on DHUDase. Moreover, CNDP did not inhibit uridine kinase, thymidine kinase, or pyrimidine phosphoribosyltransferase. Coadministration of CNDP with 1-ethoxymethyl-5-fluorouracil (EM-FU) to rats with Yoshida sarcoma elevated the level of 5-FU in both the blood and the tumor and enhanced the antitumor effect of EM-FU. These findings indicated that CNDP would be a useful chemical modulator in chemotherapy with 5-FU or its prodrugs.
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PMID:3-Cyano-2,6-dihydroxypyridine (CNDP), a new potent inhibitor of dihydrouracil dehydrogenase. 813 51


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