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Journal of Chromatography. B,... Apr 2004A sensitive method was developed for quantitation of the cytotoxic antibiotic l-alanosine in human plasma. Alanosine was extracted from plasma by anion-exchange solid...
A sensitive method was developed for quantitation of the cytotoxic antibiotic l-alanosine in human plasma. Alanosine was extracted from plasma by anion-exchange solid phase extraction, derivatized with dansyl chloride and analyzed by liquid chromatography-tandem mass spectrometry using atmospheric pressure chemical ionization in negative mode. Dansylation led to 50-fold improvement of method sensitivity over non-dansylated alanosine with a resulting 20 ng/ml limit of alanosine quantitation in plasma being achieved. The method was validated and applied for clinical studies of alanosine administered to cancer patients.
Topics: Alanine; Antibiotics, Antineoplastic; Antineoplastic Agents; Chromatography, Ion Exchange; Mass Spectrometry; Sensitivity and Specificity
PubMed: 15063341
DOI: 10.1016/j.jchromb.2004.01.003 -
Pharmacology & Therapeutics 1990The preclinical pharmacology, antitumor activity and toxicity of seven of the more important amino acid analogs, with antineoplastic activity, is discussed in this... (Review)
Review
The preclinical pharmacology, antitumor activity and toxicity of seven of the more important amino acid analogs, with antineoplastic activity, is discussed in this review. Three of these compounds are antagonists of L-glutamine: acivicin, DON and azaserine; and two are analogs of L-aspartic acid: PALA and L-alanosine. All five of these antimetabolites interrupt cellular nucleotide synthesis and thereby halt the formation of DNA and/or RNA in the tumor cell. The remaining two compounds, buthionine sulfoximine and difluoromethylornithine, are inhibitors of glutathione and polyamine synthesis, respectively, with limited intrinsic antitumor activity; however, because of their powerful biochemical actions and their low systemic toxicities, they are being evaluated as chemotherapeutic adjuncts to or modulators of other more toxic antineoplastic agents.
Topics: Amino Acids; Animals; Antineoplastic Agents; Aspartic Acid; Buthionine Sulfoximine; Eflornithine; Glutamine; Humans; Methionine Sulfoximine
PubMed: 2108451
DOI: 10.1016/0163-7258(90)90094-i -
Journal of Clinical Oncology : Official... Jul 1987We conducted parallel phase II trials of cimetidine as a single agent and the combination N-phosphonacetyl-L-aspartate (PALA) plus L-alanosine among 40 previously... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
We conducted parallel phase II trials of cimetidine as a single agent and the combination N-phosphonacetyl-L-aspartate (PALA) plus L-alanosine among 40 previously untreated patients with biopsy-proven, measurable disseminated malignant melanoma. We did not design the trial to be a comparative assessment of the two regimens. Among 19 patients treated with cimetidine, 300 mg orally four times daily, there was one complete response of extensive pleural and pulmonary metastases for 16+ months and two partial regressions of soft tissue lesions for 7 and 21+ months, respectively. Among 21 patients treated with the combination regimen, there was only one partial response in soft tissue for 1 month. The median times to progression and death were 1.4 and 6 months, respectively, for cimetidine, and 1.3 and 4 months, respectively, from the combination of PALA plus L-alanosine. Among patients who progressed on initial treatment, there were no responses in 12 who received crossover therapy with cimetidine and 11 with the combination regimen. Two patients treated with the combination program had severe stomatitis, two developed renal failure, and one had severe leukopenia and thrombocytopenia. Recognizing the limitations of small sample size, these early observations suggest that cimetidine may have intriguing implications in the management of disseminated malignant melanoma.
Topics: Alanine; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Cimetidine; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Melanoma; Middle Aged; Phosphonoacetic Acid; Pleural Neoplasms; Soft Tissue Neoplasms
PubMed: 3598611
DOI: 10.1200/JCO.1987.5.7.1078 -
Investigational New Drugs Feb 1991
Clinical Trial
Topics: Adenocarcinoma; Adult; Aged; Alanine; Antibiotics, Antineoplastic; Breast Neoplasms; Drug Evaluation; Female; Humans; Middle Aged
PubMed: 2026487
DOI: 10.1007/BF00194553 -
Biochemical Pharmacology Feb 1980
Topics: Adenosine Triphosphate; Alanine; Amino Acids; Animals; Antineoplastic Agents; Aspartic Acid; Biological Transport, Active; DNA; Glutamates; Inosine Monophosphate; Liver; Male; Mice; Nitrosamines
PubMed: 7362636
DOI: 10.1016/0006-2952(80)90333-0 -
Pharmacology 1970
Topics: Animals; Anti-Bacterial Agents; Antibody Formation; Antibody-Producing Cells; Erythrocytes; Female; Hemolysin Proteins; Immune Tolerance; Immunization; Immunosuppressive Agents; Male; Mice; Sheep; Streptomyces
PubMed: 5462270
DOI: 10.1159/000136075 -
Cancer Research Aug 2005SLC7A11 (xCT), together with SLC3A2 (4F2hc), encodes the heterodimeric amino acid transport system x(c)-, which mediates cystine-glutamate exchange and thereby regulates...
SLC7A11 (xCT), together with SLC3A2 (4F2hc), encodes the heterodimeric amino acid transport system x(c)-, which mediates cystine-glutamate exchange and thereby regulates intracellular glutathione levels. We used microarrays to analyze gene expression of transporters in 60 human cancer cell lines used by the National Cancer Institute for drug screening (NCI-60). The expression of SLC7A11 showed significant correlation with that of SLC3A2 (r = 0.66), which in turn correlated with SLC7A5 (r = 0.68), another known partner for SLC3A2, and with T1A-2 (r = 0.60; all P < 0.0001). Linking expression of SLC7A11 with potency of 1,400 candidate anticancer drugs identified 39 showing positive correlations, e.g., amino acid analogue, L-alanosine, and 296 with negative correlations, e.g., geldanamycin. However, no significant correlation was observed with the geldanamycin analogue 17-allylamino, 17-demethoxygeldanamycin (17-AAG). Inhibition of transport system x(c)- with glutamate or (S)-4-carboxyphenylglycine in lung A549 and HOP-62, and ovarian SK-OV-3 cells, reduced the potency of L-alanosine and lowered intracellular glutathione levels. This further resulted in increased potency of geldanamycin, with no effect on 17-AAG. Down-regulation of SLC7A11 by small interfering RNA affected drug potencies similarly to transport inhibitors. The inhibitor of gamma-glutamylcysteine synthetase, buthionine sulfoximine, also decreased intracellular glutathione levels and enhanced potency of geldanamycin, but did not affect L-alanosine. These results indicate that SLC7A11 mediates cellular uptake of L-alanosine but confers resistance to geldanamycin by supplying cystine for glutathione maintenance. SLC7A11 expression could serve as a predictor of cellular response to L-alanosine and glutathione-mediated resistance to geldanamycin, yielding a potential target for increasing chemosensitivity to multiple drugs.
Topics: Amino Acid Transport System y+; Antimetabolites, Antineoplastic; Buthionine Sulfoximine; Cell Line, Tumor; Cystine; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Glutathione; Humans; Neoplasms; RNA, Small Interfering
PubMed: 16103098
DOI: 10.1158/0008-5472.CAN-04-4267 -
Somatic Cell and Molecular Genetics Mar 1989Human DNA was used to transform adenosine kinase (AK)-deficient BHK cells followed by selection of AK+ cells in medium containing alanosine, adenosine, and uridine (AAU...
Human DNA was used to transform adenosine kinase (AK)-deficient BHK cells followed by selection of AK+ cells in medium containing alanosine, adenosine, and uridine (AAU medium). Twenty AAUr isolates were analyzed, and none of them contained AK activity. Several purine salvage enzymes were, however, found to be affected in these cells. The levels of hypoxanthine-guanine phosphoribosyltransferase and adenylosuccinate synthetase activities were elevated, while the adenylosuccinase activity was reduced. AAU-resistance may be explained by elevated activity of adenylosuccinate synthetase to overcome the alanosine block; thus AAUr cells were able to convert exogenous adenosine----inosine----hypoxanthine----IMP----AMPS----AMP. Moreover, these AAUr cells required exogenous purines for growth. HPLC analyses of endogenous nucleotide pools of AAUr cells showed that the levels of adenine nucleotides have diminished to less than 10% of the parental levels. These results suggest that the AAU-resistant mutation, which elicits pleiotropic phenotypes in BHK cells, affects an important component in the regulation of adenine nucleotide synthesis. By including erthyro-9-(2-hydroxy-3-nonyl)adenine in the AAU medium (renamed as AAUE medium) to block deamination of adenosine, AK+ BHK cells were isolated.
Topics: Adenine; Adenine Nucleotides; Adenosine; Adenosine Kinase; Adenylosuccinate Lyase; Adenylosuccinate Synthase; Alanine; Animals; Cells, Cultured; Chromatography, High Pressure Liquid; Cricetinae; Culture Media; Humans; Hypoxanthine Phosphoribosyltransferase; Mutation; Phosphotransferases; Purines; Selection, Genetic; Transformation, Genetic; Uridine
PubMed: 2538926
DOI: 10.1007/BF01535070 -
Biochemistry Dec 1985L-Alanosine, an antibiotic produced by Streptomyces alanosinicus, can be used by Escherichia coli aspartate transcarbamylase as a substrate instead of L-aspartate. The...
L-Alanosine, an antibiotic produced by Streptomyces alanosinicus, can be used by Escherichia coli aspartate transcarbamylase as a substrate instead of L-aspartate. The Michaelis constant of the catalytic subunit for this analogue is about 10 times higher than that for the physiological substrate, and the catalytic constant is about 30 times lower. The saturation curve of the native enzyme for L-alanosine indicates the lack of homotropic cooperative interactions between the catalytic sites for the utilization of this compound. It appears therefore that L-alanosine is unable to promote the allosteric transition. However, N-(phosphonoacetyl)-L-aspartate, a "bisubstrate analogue" of the physiological substrates, stimulates the reaction. This phenomenon is very similar to that reported by Foote and Lipscomb [Foote, J., & Lipscomb, W. N. (1981) J. Biol. Chem. 256, 11428-11433] concerning the reverse reaction using carbamylaspartate. The reaction is normally sensitive to the physiological effectors ATP and CTP. The significance of these results for the mechanism of the allosteric regulation is discussed.
Topics: Alanine; Antibiotics, Antineoplastic; Aspartate Carbamoyltransferase; Aspartic Acid; Carbon Radioisotopes; Escherichia coli; Hydrogen-Ion Concentration; Kinetics; Molecular Conformation; Radioisotope Dilution Technique; Substrate Specificity
PubMed: 3910096
DOI: 10.1021/bi00346a025 -
Drug Metabolism Reviews 1983Dose-dependent metabolism is seen for a number of anticancer drugs, and they provide examples of several different types of dose-dependent metabolic processes.... (Review)
Review
Dose-dependent metabolism is seen for a number of anticancer drugs, and they provide examples of several different types of dose-dependent metabolic processes. Arabinosyl cytosine and 5-fluorouracil are drugs whose catabolism is saturated at high doses. Therapeutic response to both drugs has been linked to plasma concentration of parent compound, and a nonlinear dose-response relationships might exist at high doses. L-Alanosine also appears to exhibit saturable metabolism at high doses, and this might be responsible for the rapid onset of L-alanosine toxicity as the dose is increased. Isophosphamide is a drug which requires metabolic activation to exert its biological effect, and saturation of metabolism seen at high dose could lead to a plateau in the dose-response relationship. Thymidine exhibits saturation of metabolism at high doses due in part to product inhibition of metabolism. Product inhibition of metabolism has also been suggested for arabinosyl cytosine. Plasma elimination of thymidine and possible elimination of 6-diazo-5-oxo-L-norleucine exhibit characteristics of a dose-dependent "memory" effect. Dose-dependent metabolism of methotrexate is unusual in that formation of the presumed toxic metabolite increases with increase in dose and is associated with a qualitative change in the pattern of drug toxicity at high compared to low doses of drug. The relationship between dose and toxicity of drugs and other foreign compounds is poorly understood in man. Anticancer drugs are one of the few classes of compounds where the relationship of toxicity to dose is reasonably well documented in human subjects. Saturation of metabolism leading to dose-dependent pharmacokinetics occurs with several anticancer drugs, and different types of dose-dependent metabolism have been covered in this review. An attempt has been made to show how dose-dependent metabolism of anticancer drugs might relate to their toxicity. Principles of dose-dependent toxicity seen with anticancer drugs might usefully be applied to other classes of compounds, particularly compounds exhibiting cytotoxicity but also other forms of toxicity. Dose-dependent metabolism could also be important in determining the therapeutic effect of anticancer drugs, and application of principles of dose-dependent metabolism to the development of new chemotherapeutic regimens migh lead to more effective cancer chemotherapy.
Topics: Alanine; Antineoplastic Agents; Cytarabine; Dose-Response Relationship, Drug; Doxorubicin; Fluorouracil; Humans; Ifosfamide; Kinetics; Methotrexate; Thymidine
PubMed: 6373208
DOI: 10.3109/03602538308991425