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At least 19 recordsLinked to original sources
PubMed1994

Gene technology-based antimetabolite design: the use of an in vitro protein expression system to facilitate antimetabolite design for virally-induced human diseases and malignant conditions.

A precondition for the chemotherapeutic treatment of a variety of virally-induced human diseases and malignant conditions is a highly selective interaction of the drug molecule to be used with it's biological target. To ensure the development of novel, effective drugs, it is essential that the biological target is well characterised with regard to it's structure and activity. Such characterisation relies upon adequate amounts of pure target being available. One of the most important enzymatic importers for antimetabolites is the enzyme thymidine kinase. In this article an in vitro protein expression system is described which facilitates the production of milligram amounts of pure and biologically active thymidine kinase, from a number of important biological sources. Results have shown that the in vitro produced enzyme has the exact biochemical propeties of the in vivo enzyme. Thus the in vitro protein expression system is an ideal vechicle to facilitate an in depth investigation of the enzyme's biological properties.

Journal Article↗
PubMed1993

The kinetic properties of switch antimetabolites.

BACKGROUND: Maintaining homeostasis is the biological function of negative feedback, a process that plays a well-understood role in the biochemistry of antimetabolite drugs. An equally important property of living systems--the ability to respond to external stimuli by switching rapidly from one state to another--is mediated by positive feedback. Kinetic analysis of multi-enzyme biochemical pathways has shown that pathways containing positive feedback coupled with negative feedback may act as biochemical switching systems in which multiple steady states are possible. PURPOSE: A computer model was used to study the kinetic effects of antimetabolites that inhibit biochemical pathways at positive feedback sites and to determine whether the kinetics of such systems differed from those of classical antimetabolites. METHODS: Kinetics were simulated by microcomputer to model the effects of inhibitors on a simplified metabolic pathway. RESULTS: Antimetabolite drugs that act at positive feedback sites are predicted to display highly nonclassical properties. Three nonclassical properties are kinetically possible. First, the drugs may switch off the pathway at substoichiometric concentrations; classical antimetabolites require stoichiometric levels and sometimes much more. Second, instead of demonstrating classical continuous inhibition, antimetabolite drugs that act at positive feedback sites may give "all-or-none" dose-response curves with discontinuity at a specific value. Inhibitor concentrations below this value would have no overall effect on the system, while inhibitor concentrations at or above this value would give an abrupt transition to an inhibited steady state. Third, the inhibited system may show hysteresis and remain switched off after the inhibitor is removed. CONCLUSIONS: These findings suggest that antimetabolites acting at switch points could have kinetic properties very different from those of classical antimetabolites and could provide a noncytotoxic method of switching off pathways in neoplastic cells, perhaps leading to cell stasis. IMPLICATIONS: Experimental validation of these conclusions will require identification of the positive feedback sites of metabolic and signaling pathways and exploration of the effects of inhibitors of these sites. The properties of "switch antimetabolites" should prompt a search for new kinds of targets for drug design.

Antimetabolites, Antineoplastic↗
PubMed2001

A review of dose-limiting events in phase I trials: antimetabolites show unpredictable relationships between dose and toxicity.

INTRODUCTION: In a sample of NCIC CTG phase I trials we noted that studies of antimetabolites were frequently confounded by the occurrence of dose-limiting toxicities (DLT) at doses well below those ultimately recommended (recommended dose, RD) for further study, necessitating frequent expansion of dose levels and usually a change to more conservative dose escalation. This slowed development, exposed patients to ineffective doses of drugs, and raises concerns about the safety of current trial designs which include a single patient per dose level. Conversely, some patients treated at the RD may be receiving inadequate doses of anticancer drugs. To determine if this was a general phenomenon, we undertook a review of the results of a large group of phase I trials of cytotoxic agents. METHODS: Starting dose (SD), number of dose levels, dose at first DLT (D-DLT), maximum tolerated doses (MTD, dose at which DLT is seen in two or more patients) and RD were extracted from the NCI-Canada phase I trial database, and from a literature survey of phase I studies published between 1985 and 1999. Combination phase I and phase Ib studies were excluded. RESULTS: The review included 33 trials with antimetabolites and 60 with other cytotoxic agents. The median ratio D-DLT/MTD was 0.33 for antimetabolites and 0.75 for other cytotoxic agents (P < 0.01). Similarly, the median ratio D-DLT/RD was 0.43 for antimetabolites and 1 for other cytotoxic agents (P < 0.01). The median number of dose levels tested was nine for antimetabolites and six for other cytotoxic agents. DISCUSSION: Statistically significant differences in the ratios D-DLT/MTD and D-DLT/RD between antimetabolites and other cytotoxic compounds were noted, confirming our initial observations that unpredictable DLT occurs earlier and at lower dose levels in phase I clinical trials of antimetabolites than would be expected as compared to other classes ofcytotoxic agents. Toxicity thus appears to be incompletely predicted by dose alone for antimetabolites. DLT may occur in certain patients at doses well below the RD. Current phase I design may not be ideal for development of these compounds, and should focus on pharmacodynamic endpoints in addition to traditional pharmacokinetic and clinical endpoints.

Antimetabolites, Antineoplastic↗
PubMed1993

Changes in glycosylation of L1210 cells after exposure to various antimetabolites.

This study establishes that antimetabolites do have the potency to change cellular glycosylation, as was suggested in our previous review (Eur J Cancer 1990, 26, 516-523). Murine leukaemia L1210 cells were exposed to various antimetabolites under non-lethal conditions. The antimetabolites 5-fluorouracil (5FU), arabinofuranosylcytosine (AraC), methotrexate (MTX) and 6-mercaptopurine (6MP), but not 6-thioguanine, induced considerable changes in the metabolic incorporation of radioactively labelled monosaccharides. Each antimetabolite exhibited a different effect. Significant differences were found between the radioactivity incorporated from the monosaccharides glucosamine, fucose, mannose and galactose, relative to control values. Polyacrylamide gel electrophoresis indicated that changes were induced in the glycosylation of individual glycoproteins. 5FU, AraC, MTX and 6MP all influenced both pyrimidine- and purine-mediated sugar incorporation. This excludes, therefore, direct effects of the antimetabolites on their analogue nucleotide-sugars. The antimetabolite-induced changes in glycosylation did not directly correlate with the observed cell-cycle effects of the antimetabolites.

Animals↗
PubMed1998

Correction of lower eyelid retraction in thyroid eye disease: a randomised controlled trial of retractor tenotomy with adjuvant antimetabolite versus scleral graft.

BACKGROUND/AIMS: Lower eyelid retraction in thyroid eye disease contributes to ocular discomfort and an unsightly appearance, especially if asymmetrical. The use of donor scleral grafts is effective in lengthening the lower eyelids but carries a risk of virus transmission. Other techniques, including those which do not use grafts, need to be compared with scleral grafts. Recurrent retraction is a recognised complication of thyroid eyelid surgery; therefore, the authors investigated the use of antimetabolites to reduce postoperative fibrosis. METHODS: In this prospective randomised controlled trial of 25 patients (35 eyelids), the use of donor sclera in 20 lower eyelids (13 patients) was compared with partial tenotomy of the anterior part of the lower eyelid retractors (ALER) with adjuvant peroperative antimetabolite in 15 lower eyelids (12 patients). A 5 minute peroperative application of either 5-fluorouracil (25 mg/ml) in nine lower eyelids (eight patients) or mitomycin C (0.2 mg/ml) in six lower eyelids (four patients) was used to focally inhibit fibroblasts. Follow up ranged from 3 to 18 months (mean 7.8). RESULTS: One month after surgery the results of both groups were similar. However, at 3 months after surgery the results of scleral grafting were better than tenotomy with antimetabolites: 3/12 patients (25%) treated with tenotomy and adjuvant antimetabolite required subsequent surgery using grafts for correction of recurrent retraction. There were no significant complications associated with the use of antimetabolites in the eyelid in the doses used in this study. CONCLUSIONS: This randomised prospective trial shows that donor scleral grafts were more effective in the long term than partial tenotomy with adjuvant antimetabolite in the correction of lower eyelid retraction associated with thyroid eye disease. The use of peroperative antimetabolites in the lower eyelid was safe.

Adult↗
PubMed1995

[Usefulness of adjuvant chemotherapy with antimetabolites for cervical invasive cancer].

A series of 584 patients with cervical invasive cancer were included in the retrospective study on the efficacy of long-term oral maintenance chemotherapy with antimetabolites (Fluorouracil or Tegaful). The patients were histologically classified into the squamous cell carcinoma (SCC) group and the adenocarcinoma (AD) group. In the SCC group (n = 518), 163 patients were given more than 300 mg/day of antimetabolite tablets for one year or more after the main therapy (hysterectomy or pelvic irradiation). In the AD group (n = 66), 36 patients were treated with the same dose of antimetabolites. The Kaplan-Meier overall and cancer specific survival analysis estimates that the chronic administration of antimetabolites did not improve the cumulative 5-year survival in the SCC group. In contrast, the cumulative 5-year survival rate in the AD group treated with antimetabolites (88%) was significantly higher than that without chemotherapy (64%) by Kaplan-Meier analysis. This significant improvement in the survival rate in the AD group due to antimetabolites was notable in patients in FIGO stage I or II treated with radical or semiradical hysterectomy, these results indicate that oral adjuvant chemotherapy with antimetabolites is useful for cervical adenocarcinoma, but not for squamous cell carcinoma.

Adenocarcinoma↗
PubMed2000

Success criteria and success rates in trabeculectomy with and without intraoperative antimetabolites using intensified postoperative care (IPC).

PURPOSE: To define the success rate of trabeculectomy for surgical treatment of glaucoma under intensified postoperative care (IPC) conditions in cases of severe visual field damage or progression of visual field loss. METHODS: In a retrospective study, we evaluated the outcome of trabeculectomy in 99 eyes of 99 patients from October 1995 to June 1997. In 23 eyes, antimetabolites were used intraoperatively. Regarding intraocular pressure (IOP), success was defined as lowering the preoperative, maximally treated IOP by more than 20% in addition to a postoperative IOP level lower than 21 mmHg without using further glaucoma medication. Success rate was defined by stabilisation of visual acuity and visual field in addition to IOP reduction. RESULTS: The postoperative IOP was 14.7 mmHg (+/- 3.4 mmHg) following standard trabeculectomy (preoperative IOP 24.3 +/- 6.7 mmHg) and 15.8 mmHg (+/- 4.9 mmHg) following trabeculectomy with intraoperative antimetabolites (preoperative IOP 27.0 +/- 9.5 mmHg). The success rate concerning the IOP was 83% in standard trabeculectomy and 74% following trabeculectomy with intraoperative antimetabolites. The visual acuity showed stabilisation in 93% of cases following standard trabeculectomy and in 100% following trabeculectomy with intraoperative antimetabolites. The visual field showed stabilisation according to the Aulhorn criteria in 95% and 94% of cases following standard trabeculectomy and trabeculectomy with intraoperative antimetabolites, respectively. The total success rate using all criteria together was 76% following standard trabeculectomy and 74% following trabeculectomy with intraoperative antimetabolites. CONCLUSION: The overall outcome after trabeculectomy is good with appropriate follow-up and timely decisions for after-treatment to ensure good development of the filtering bleb.

Adult↗
PubMed1981

Busulfan, antimetabolites, radiotherapy, and cost of treatment in chronic myelocytic leukemia. A non-controlled, non-randomized monocenter study with historical controls.

The possibilities were studied of achieving remission more quickly, of preventing conceivably alkylator-induced blastic transformation, and of prolonging survival in chronic myelocytic leukemia (CML) by replacing busulfan induction of remission by antimetabolite induction. The promise of the project was not considered to merit a prospective, controlled, randomized multicenter study, and therefore a retrospective, non-controlled, non-randomized pilot study was elected. One antimetabolite-treated group (cytosine arabinoside and thioguanine) and two busulfan-treated patient groups were studied. One of the latter two groups received splenic irradiation in addition to busulfan. No statistically significant differences between the busulfan groups were found in the time to achieve remission, the length of the first, unmaintained remission, the frequency of blastic metamorphosis or the cost of treatment. The actuarial survival curves of all three groups were similar. The antimetabolite induction was well tolerated and led to a statistically significantly more rapid remission than busulfan. However, the remission was significantly shorter, and no significant difference in the frequency of blastic metamorphosis was found between the groups. The median cost (from diagnosis to death) of hospitalization, visits, treatment, and part of the loss of production was approximately 106 000 Sw. cr. in the busulfan + radiotherapy group, 116 000 in the busulfan group, and 178 000 in the antimetabolite group. It is suggested that a prospective, randomized, controlled study could confirm that the present antimetabolite induction may lead to a more rapid remission induction in CML without more side-effects. However, to prevent early relapse, antimetabolite induction should be combined with busulfan maintenance treatment.

Busulfan↗
PubMed1998

Occlusive ligature and standardized fenestration of a Baerveldt tube with and without antimetabolites for early postoperative intraocular pressure control.

OBJECTIVE: To determine the effectiveness of a surgical modification for a nonvalved aqueous tube shunt in controlling intraocular pressure (IOP) in the early postoperative period. The effect of antimetabolite use on IOP also was studied. DESIGN: A retrospective study of consecutive patients who underwent modified Baerveldt 350-mm2 implant with varied, nonrandomized, exposure to antimetabolites. PARTICIPANTS: Fifty-one eyes of 46 patients with uncontrolled glaucoma were examined. INTERVENTION: Identical surgical modification of a Baerveldt 350-mm2 tube was performed in all cases and consisted of placement of an occlusive 7-0 polyglactin suture just anterior to the plate followed by a through-and-through penetration of the tube just anterior to the occlusive ligature with a standardized 15 degrees blade. Seventeen eyes were not exposed to antimetabolite, while 2 groups of 17 eyes had 3 minutes' episcleral exposure to either 5-fluorouracil 50 mg/ml or mitomycin C 0.4 mg/ml at the location corresponding to the fenestration. The Tenon's layer and conjunctiva were not exposed because of concerns regarding conjunctival erosion over the device. MAIN OUTCOME MEASURE: Intraocular pressure and number of antiglaucoma medications required were analyzed. RESULTS: For the group, mean IOP before surgery and on postoperative days 1, 4, 10, 21, 42, 63, 84, and 112 was (in millimeters of mercury) 34.6, 20.1, 17.0, 17.2, 22.0, 17.3, 18.7, 17.4, and 15.6, respectively. There was an elevation of IOP at day 21 relative to fibrotic blockage of the fenestration before suture autolysis. This was temporized with antiglaucoma medication until suture autolysis occurred or treated with laser suture lysis (8 eyes). On day 1, hypotony occurred in 3 (6%) eyes whereas IOP greater than 30 mmHg was observed in 13 (26%) eyes. By day 10, the frequency had decreased to one (2.1 %) eye and three (6.4%) eyes, respectively. The use of antimetabolites did not result in lower IOP or less medication needed for any group at any interval (analysis of variance). CONCLUSION: This modification of a nonvalved glaucoma tube shunt device provides adequate IOP control in the early postoperative period with a low rate of hypotony and surgical complications. If elevation of IOP occurs before suture autolysis, it generally is well controlled by antiglaucoma medications or laser suture lysis. Antimetabolite exposure did not influence early postoperative IOP in this study.

Aged↗
PubMed1976

[Search for antibiotic antimetabolites].

Special media have been developed during the past years, which provided detection of new antibiotics with the properties of antimetabolites produced by microorganisms. Antimetabolites of amino acids, vitamins and nucleic acids were found among the antimetabolite antibiotics. The antimetabolites of nucleic acids with an antitumor activity were most interesting. This group of the compounds included 5-asacytidin and antibiotic 1719 identical to azotomycin.

Actinomycetales↗
PubMed1997

Successful treatment of relapsed infant acute lymphoblastic leukemia with intensive antimetabolite-based chemotherapy.

PURPOSE: The treatment of infant acute lymphoblastic leukemia (ALL) continues to be a significant challenge for pediatric oncologists due to the high incidence of early relapses. Salvage regimens used to date have met limited success. We describe two cases of relapsed infant ALL who have achieved long-term survival with an intensive antimetabolite-based salvage regimen. PATIENTS AND METHODS: Two consecutive infants with relapsed ALL presented at our institution and were treated with an antimetabolite-based regimen. Both cases exhibited clinical and biological phenotypes previously associated with infantile ALL. RESULTS: Both patients have achieved prolonged and sustained remissions 48 and 30 months EFS respectively following therapy with intensive antimetabolite-based salvage regimen. CONCLUSIONS: An intensive multiagent antimetabolite based salvage regimen resulted in prolonged EFS in two cases of relapsed infant ALL. Dose intensification was achieved by administering repeated cycles of the same treatment schema using high dose chemotherapy throughout therapy. These infants were spared prophylactic cranial irradiation without a negative impact on outcome. The use of L-asparaginase, timed after high-dose Cytarabine (ARA-C) throughout therapy, might have contributed to their cure.

Antimetabolites, Antineoplastic↗