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  • 1
    Electronic Resource
    Electronic Resource
    Phase II trial of PALA and 6-methylmercaptopurine riboside (MMPR) in combination with 5-fluorouracil in advanced pancreatic cancer (1994)
    Springer
    Investigational new drugs 12 (1994), S. 319-321 
    Details
    ISSN: 1573-0646
    Keywords: phase II ; PALA ; 5-FU ; MMPR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The biochemical modulators PALA, an inhibitor of aspartate transcarbamylase which depletes uridine nucleotide pools, and 6-methylmercaptopurine riboside (MMPR) which inhibits purine metabolism, selectively potentiate the antitumor activity of 5-fluorouracil (5-FU) in preclinical models. Based on a phase I trial of this combination, we performed a phase II trial in patients with advanced pancreatic cancer. PALA 250 mg/m2 was administered i.v. on day 1, followed 24h later by MMPR 150 mg/m2 as a bolus i.v. injection, and 5-FU 2300 mg/m2 by 24h infusion. Treatments were repeated weekly. Seventeen patients, all previously untreated with chemotherapy, were entered, of whom 14 are evaluable for response. Toxicity ≥ grade 2 included nausea (6/17), vomiting (4/17), diarrhea (3/17), stomatitis (5/17), and neurotoxicity (2/17). Among 14 evaluable patients there were no partial responses, and two patients with stable disease. Pretreatment with PALA and MMPR is insufficient to enhance the activity of 5-FU in pancreatic cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873047
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  • 2
    Electronic Resource
    Electronic Resource
    Tiazofurin: A new antitumor agent (1984)
    Springer
    Investigational new drugs 2 (1984), S. 79-84 
    Details
    ISSN: 1573-0646
    Keywords: tiazofurin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tiazofurin is an interesting drug now entering Phase I trials, with marked preclinical antitumor activity against P388 and L1210 leukemias, and the Lewis lung carcinoma. Schedule dependency favoring frequent administration has been noted. The drug has a novel mechanism of action, being metabolized to an inhibitory cofactor of inosine monophosphate dehydrogenase. Tiazofurin is widely distributed after i.v. administration exhibiting a triphasic pattern of plasma decay, with a terminal half-life of 3–16 h in the three species studied. Approximately 90% of the drug was excreted unchanged in the urine within 24 h. A significant potential for the slower release of intracellularly retained drug exists. Anticipated organ toxicities based on the studies described include myelotoxicity, hepatotoxicity and nephrotoxicity. These were mild and reversible at lower doses, and were not seen at levels corresponding to the starting doses in man. A potential for hyperuricemia exists; this should be easily controllable by the use of allopurinol, without compromising the drug's antitumor effect. Phase I trials under the sponsorship of the NCI are underway in a number of institutions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173791
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  • 3
    Electronic Resource
    Electronic Resource
    5-methyltetrahydrohomofolate (1987)
    Springer
    Investigational new drugs 5 (1987), S. 215-218 
    Details
    ISSN: 1573-0646
    Keywords: 5-methyltetrahydrohomofolate ; antimetabolite ; antifolate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 5-methyltetrahydrohomofolate was developed in the 1970's as an antifolate with the potential to overcome methotrexate resistance. This review summarizes the preclinical and clinical data which have accumulated to date. It is concluded that more recent, better characterized antifolates offer greater potential in achieving the goals for which this drug was introduced.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00175290
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  • 4
    Electronic Resource
    Electronic Resource
    Pyrazole: preclinical reassessment (1988)
    Springer
    Investigational new drugs 6 (1988), S. 305-310 
    Details
    ISSN: 1573-0646
    Keywords: pyrazole ; alcohol dehydrogenase ; anticancer drug ; microsomal enzyme inducer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pyrazole (NSC-45410) is a low molecular weight, heterocyclic compound which has been considered for reevaluation in the clinic as a potential cytotoxic agent (Fig. 1). Discovered in 1893 [1], pyrazole is best known as an inhibitor of liver alcohol dehydrogenase (ki= 0.2 uM), and as a result, has been used extensively in studies of alcohol metabolism [2]. In 1960, pyrazole was identified as being active in preclinical antitumor models [3], which led to preliminary clinical testing [4,5]. The early Phase I studies were not followed by disease specific Phase II trials, and the clinical activity of the drug has never been evaluated. This omission was noted by the National Cancer Institute's Project for the Review of Old Drugs (PROD), at which time it was also noted that pyrazole is selectively toxic to thyroid tissue in an animal model [6]. Hence, interest in pyrazole was revived for two reasons: (a) failure to screen it for clinical activity in the 1960's, and (b) current interest in discovering drugs with selective toxicity to specific tissues for evaluation of their activity in malignancies arising in the target tissue. In this review, we summarize the evidence which has accumulated concerning pyrazole's potential role as an anticancer agent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173649
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  • 5
    Electronic Resource
    Electronic Resource
    Phase II trial of topotecan in advanced or metastatic adenocarcinoma of the pancreas (1995)
    Springer
    Investigational new drugs 13 (1995), S. 347-354 
    Details
    ISSN: 1573-0646
    Keywords: pancreatic cancer ; phase II study ; topotecan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Purpose A phase II trial of topotecan, an inhibitor of topoisomerase I, was conducted in patients with advanced or metastatic adenocarcinoma of the pancreas to determine the activity and toxicity of topotecan. Patients and Materials 35 patients, previously untreated with chemotherapy, received topotecan 1.5 mg/ m2/d for five days intravenously and repeated every 21 days. Patients were assessed for response after 3 cycles. Those with either clinical response or stable disease received additional cycles of the drug until toxicity developed or disease progression occurred. Results Among 30 patients evaluable for response there were no complete responses and 3 partial responses (10%) for a total response rate of 10% (95% confidence interval = 0–20.6%). Stable disease for at least eight weeks was seen in 11 patients (36%). Median survival was 19 weeks (95% confidence interval 11 to 26 weeks). Therapy was generally well tolerated, with reversible granulocytopenia being the most common toxicity. Conclusion Topotecan given on a 5 day, short infusion schedule, demonstrated limited activity in pancreatic carcinoma with minimal toxicity. Further exploration of topotecan in pancreatic carcinoma using different dosing schedules is warranted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873143
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  • 6
    Electronic Resource
    Electronic Resource
    Phase II study of amonafide (Nafidamide, NSC 308847) in advanced colorectal cancer (1991)
    Springer
    Investigational new drugs 9 (1991), S. 65-67 
    Details
    ISSN: 1573-0646
    Keywords: amonafide ; NSC 308847 ; benzisoquinoline-1,3-dione ; colorectal cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Amonafide, a benzisoquinoline-1,3-dione with anti-tumor activity in preclinical screens, was administered to patients with recurrent or metastatic bidimensionally measurable colorectal cancer. Fourteen patients with no prior chemotherapy for advanced disease, performance status 0–1, and normal bone marrow, renal, and hepatic function were entered. Amonafide 300 mg/m2 was administered intravenously over 1 hour daily for five consecutive days; courses were repeated every three weeks. The major side effect was neutropenia: Grade 3 or 4 toxicity occurred in 5/14 patients. Other toxicities included nausea and vomiting, flulike symptoms, fever, rash and alopecia. Three patients had stable disease, but there were no responses observed. Amonafide at this dose and schedule has no activity in the treatment of colorectal cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194547
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  • 7
    Electronic Resource
    Electronic Resource
    Phase II study of amonafide in advanced and recurrent sarcoma patients (1992)
    Springer
    Investigational new drugs 10 (1992), S. 99-101 
    Details
    ISSN: 1573-0646
    Keywords: amonafide ; benzisoquinoline-1-3-dione ; sarcoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The activity of amonafide, a benzisoquinoline-1,3-dione, was assessed in 15 patients with advanced or recurrent sarcoma (11 previously treated). Eligible patients had ECOG performance status 0–2, and acceptable renal, hepatic and bone marrow function. Amonafide 300 mg/m2 was given intravenously over one hour daily on five consecutive days, every 3 weeks. Leukopenia and granulocytopenia were the most common and severe toxicities (grade 3 or 4 toxicity in 20% and 27% of patients, respectively). Local irritation and nausea/vomiting, the most common nonhematologic toxicities, were generally mild. No objective responses were seen, though 2 patients had brief stabilization of disease. Amonafide at this dose and schedule has no activity against advanced, recurrent sarcoma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873125
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  • 8
    Electronic Resource
    Electronic Resource
    A Phase II trial of weekly infusional 5-fluorouracil in combination with lowdose leucovorin in patients with advanced colorectal cancer (1995)
    Springer
    Investigational new drugs 13 (1995), S. 229-233 
    Details
    ISSN: 1573-0646
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Exogenous leucovorin is a source of reduced folate which enhances the inhibition of thymidylate synthase that results from 5-fluorouracil (5-FU) administration. Extracellular reduced folate concentrations of 1 μM have been reported to yield maximal enzyme inhibition in several cell lines treated with 5-FUin vitro. Clinical studies indicate that low doses of leucovorin have equivalent efficacy to higher doses in successfully modulating 5-FU in the treatment of colorectal cancer. Based on pharmacokinetics at higher doses, steadystate total plasma reduced folate concentrations of 1 μM would be expected from the administration of leucovorin 50 mg/m2 by 24 h infusion. This dose was admixed with 5-FU 2300 mg/m2 and administered by 24 h infusion weekly to 38 patients with advanced colorectal cancer, of whom 32 are evaluable for response. Disease sites included liver (33 patients), lung (12 patients), and bone (4 patients). Toxicity was mild to moderate, except for grade 3 diarrhea in 5 patients, and chest pain in 2 patients. Among the 32 evaluable patients, there were 14 partial remissions for a total response rate of 44% (95% confidence interval 27–61%). The median duration of response was seven (range 1 to 20+) months, and median duration of survival 16 months. These results support the use of low doses of leucovorin to modulate weekly infusional 5-FU in colorectal cancer, and provide a basis for the integration of this regimen with other modulators of 5-FU.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00873805
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  • 9
    Electronic Resource
    Electronic Resource
    Phase I trial of fluorouracil modulation by n-phosphonacetyl-l-aspartate and 6-methylmercaptopurine ribonucleoside (MMPR), and leucovorin in patients with advanced cancer (1997)
    Springer
    Investigational new drugs 15 (1997), S. 139-145 
    Details
    ISSN: 1573-0646
    Keywords: 5-FU ; biochemical modulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed a phase I trial using a combination of three different biochemical modulators at the optimal dose established in previous clinical trials. The modulators include: phosphonacetyl-l-aspartate (PALA), which may increase 5-FU incorporation into RNA; leucovorin, which potentiates thymidylate synthase inhibition; and 6-methylmercaptopurine riboside (MMPR), which promotes the intracellular retention of fluorinated nucleotides. The treatment regimen consisted of PALA 250 mg/m2 day 1, followed 24h later by MMPR 150 mg/m2 as an iv bolus, and the initiation of a 24 hour infusion of 5-FU along with leucovorin 50 mg/m2. This regimen was repeated weekly. Doses of 5-FU were escalated in cohorts of four or more patients from 2,000 to 2,600 mg/m2. Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantly gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2600 mg/m2. There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulation value of PALA at this dose and schedule suggests that revision of this regimen be considered before Phase II trial.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005812923473
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  • 10
    Electronic Resource
    Electronic Resource
    Trimetrexate: a new antifol entering clinical trials (1985)
    Springer
    Investigational new drugs 3 (1985), S. 71-75 
    Details
    ISSN: 1573-0646
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Trimetrexate, a 2,4-diaminoquinazoline derivative, is a new antifol recently introduced into clinical trials. It differs from methotrexate principally in its transport (not carrier-mediated), and its intracellular retention (not polyglutamylated). Trimetrexate is active against tumors which are methotrexate-resistant on the basis of impaired transport, and has a broader range of antitumor activity in preclinical models. Animal studies predict toxicity principally to the central nervous system, gastrointestinal tract and bone marrow.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00176828
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