The role of β-glucuronidase in drug disposition and drug targeting in humans

Clinical Pharmacokinetics

Volumn 33, Issue 1, 1997, Pages 18-31

  Sperker, Bernhard ^a   Backman, Janne T ^a   Kroemer, Heyo K ^a  

^a DR MARGARETE FISCHER BOSCH INSTITUTE OF CLINICAL PHARMACOLOGY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BAICALIN; BETA GLUCURONIDASE; CARCINOEMBRYONIC ANTIGEN; CLOFIBRATE; DAUNORUBICIN; DIFLUNISAL; DOXORUBICIN; DRUG METABOLITE; DRUG METABOLIZING ENZYME; EPIRUBICIN; GLUCURONIDE; GLYCYRRHIZIC ACID; IMIPRAMINE; IRINOTECAN; MIDAZOLAM; MUSTARD GAS DERIVATIVE; NONSTEROID ANTIINFLAMMATORY AGENT; OXAZEPAM; PRODRUG; PROPAFENONE; PROPRANOLOL; XENOBIOTIC AGENT;

ANTIBODY DIRECTED ENZYME PRODRUG THERAPY; CHEMICAL CARCINOGENESIS; DRUG ACCUMULATION; DRUG ACTIVATION; DRUG CONJUGATION; DRUG DISPOSITION; DRUG GLUCURONIDATION; DRUG HYDROLYSIS; DRUG METABOLISM; DRUG TARGETING; DRUG TRANSFORMATION; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME MECHANISM; ENZYME SPECIFICITY; ENZYME STRUCTURE; GASTROINTESTINAL TOXICITY; HUMAN; LONG TERM CARE; PRIORITY JOURNAL; REVIEW;

EID: 0030751284     PISSN: 03125963     EISSN: None     Source Type: Journal    
DOI: 10.2165/00003088-199733010-00003     Document Type: Review

References (123)

1. Kroemer HK, Klotz U. Glucuronidation of drugs: a re-evaluation of the pharmacological significance of the conjugates and modulating factors. Clin Pharmacokinet 1992; 23 (4): 292-310
2. Miners JO, Mackenzie PI. Drug glucuronidation in humans. Pharmacol Ther 1991; 51: 347-69
3. Osborne RJ, Joel SP, Slevin ML. Analgesic activity of morphine-6-glucuronide. Lancet 1988; I: 828
4. Osborne R, Thompson P, Joel S, et al. The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol 1992; 34: 130-8
5. Bauer TM, Ritz R, Haberthür C, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet 1995; 346: 145-7
6. Sisenwine SF, Tio CO, Hadley FV, et al. Species related differences in the stereoselective glucuronidation of oxazepam. Drug Metab Dispos 1982; 10: 605-8
7. Sutfin TA, Perini GI, Molnar G, et al. Multiple-dose pharmacokinetics of impramine and its major active and conjugated metabolites in depressed patients. J Clin Psychopharmacol 1988; 8 (1): 48-53
8. Walle T, Conradi EC, Walle UK, et al. Propranolol glucuronide accumulation during long-term therapy: a proposed storage mechanism for propranolol. Clin Pharmacol Ther 1979; 26: 686-95
9. Eriksson L-O, Wählin-Boll E, Odar-Cederlöf I, et al. Influence of renal failure, rheumatoid arthritis and old age on the pharmacokinetics of diflunisal. Eur J Clin Pharmacol 1989; 36: 165-74
10. Fromm MF, Botsch S, Heinkele G, et al. Influence of renal function on the steady-state pharmacokinetics of the antiarrhythmic propafenone and its phase I and phase II metabolites. Eur J Clin Pharmacol 1995; 48: 279-83
11. Lieberman JA, Cooper TB, Suckow RF, et al. Tricyclic antidepressant and metabolite levels in chronic renal failure. Clin Pharmacol Ther 1985; 37 (3): 301-7
12. Hasselström J, Berg U, Löfgren A, et al. Long lasting respiratory depression induced by morphine-6-glocuronide. Br J Clin Pharmacol 1989; 27: 515-8
13. Meffin PJ, Zilm DM, Veenendaal JR. Reduced clofibric acid clearance in renal dysfunction is due to a futile cycle. J Pharmacol Exp Ther 1983; 227 (3): 732-8
14. Brater DC. Clinical pharmacology of NSAIDs. J Clin Pharmacol 1988; 28: 518-23
15. Brunelle FM, Verbeeck RK. Glucuronidation of diflunisal in liver and kidney microsomes of rat and man. Xenobiotica 1996; 26 (2): 123-31
16. Wakabayashi M. Beta-glucuronidases in metabolic hydrolysis. In: Fishman WH, editor. Metabolic conjugation and metabolic hydrolysis. New York: Academic Press, 1970: 519-602
17. Paigen K. Mammalian β-glucuronidase: genetics, molecular biology and cell biology. Prog Nucleic Acid Res Mol Biol 1989; 37: 155-205
18. Bosslet K, Czech J, Hoffmann D. Tumor-selective prodrug activation by fusion protein-mediated catalysis. Cancer Res 1994; 54: 2151-9
19. Henle KJ, Monson TP, Nagle WA, et al. Tumor-targeted cell killing with 8-hydroxyquinolyl-glucuronide. Radiat Res 1988; 115 (2): 373-86
20. Houba PHJ, Leenders RGG, Boven E, et al. Characterization of novel anthracycline prodrugs activated by human beta-glucuronidase for use in antibody-directed enzyme prodrug therapy. Biochem Pharmacol 1996; 52 (3): 455-63
21. Sinbababu AK, Thakker DR. Prodrugs of anticancer agents. Adv Drug Deliv Rev 1996; 19: 241-73
22. Eisenberg Jr F. The mechanism of action of beta-glucuronidase. Fed Proc Fed Am Soc Exp Biol 1959; 18: 221
23. Corrales-Hernandez JJ, Gonzalez-Buitrago JM, Pastor-Encinas I, et al. Androgen environment and beta-glucuronidase activity in the human kidney. Arch Androl 1988; 20 (3): 185-91
24. Fishman WH, Kato K, Anstiss CL, et al. Human serum β-glucuronidase; its measurement and some of its properties. Clin Chim Acta 1967; 15: 435-47
25. Sperker B, Mürdter TE, Schick M, et al. Interindividual variability in expression and activity of human β-glucuronidase in liver and kidney: consequences for drug metabolism. J Pharmacol Exp Ther 1997; 281: 914-20
26. Boyer MJ, Tannock IE. Lysosomes, lysosomal enzymes and cancer. Adv Cancer Res 1993; 60: 269-91
27. Stephens RW, Ghosh P, Taylor TK, et al. The origins and relative distribution of polysaccharidases in rheumatoid and osteoarthritic fluids. J Rheumatol 1975; 2: 393-400
28. Camisa C, Hessel A, Rossana C, et al. Autosomal dominant keratoderma, ichthyosiform dermatosis and elevated serum beta-glucuronidase. Dermatologica 1988; 177 (6): 341-7
29. Ohta H, Ono M, Sekiya C, et al. Serum immunoreactive β-glucuronidase determined by an enzyme-linked immunosorbent assay in patients with hepatic diseases. Clin Chim Acta 1992; 208 (1-2): 9-21
30. Saha AK, Glew RH, Kotler DP, et al. Elevated serum β-glucuronidase activity in acquired immunodeficiency syndrome. Clin Chim Acta 1991; 199 (3): 311-6
31. Sly WS, Quinton BA, McAlister WH, et al. Beta glucuronidase deficiency: report of clinical, radiologic and biochemical features of a new mucopolysaccharidosis. J Pediatr 1973; 82 (2): 249-57
32. Vervoort R, Islam MR, Sly WS, et al. Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII. Am J Hum Genet 1996; 58(3): 457-71
33. Vervoort R, Lissens W, Liebaers I. Molecular analysis of a patient with hydrops-fetalis caused by beta-glucuronidase deficiency, and evidence for additional pseudogenes. Hum Mutat 1993; 2 (6): 443-5
34. Shipley JM, Klinkenberg M, Wu BM, et al. Mutational analysis of a patient with mucopolysaccharidosis type VII, and identification of pseudogenes. Am J Hum Genet 1993; 52: 517-26
35. Vervoort R, Islam MR, Sly W, et al. A pseudodeficiency allele (d152n) of the human beta-glucuronidase gene. Am J Hum Genet 1995; 57 (4): 798-804
36. Miller RD, Hoffmann JW, Powell PP, et al. Cloning and characterization of the human beta-glucuronidase gene. Genomics 1990; 7 (2): 280-3
37. Speleman F, Vervoort R, Vanroy N, et al. Localization by fluorescence in situ hybridization of the human functional beta-glucuronidase gene (GUSB) to 7q11.21q11.22 and two pseudogenes to 5p13 and 5q13. Cytogenet Cell Genet 1996; 72 (1): 53-5
38. Shipley JM, Miller RD, Wu BM, et al. Analysis of the 5′ flanking region of the human beta-glucuronidase gene. Genomics 1991; 10 (4): 1009-18
39. Oshima A, Kyle JW, Miller RD, et al. Cloning, sequencing, and expression of cDNA for human beta-glucuronidase. Proc Natl Acad Sci USA 1987; 84 (3): 685-9
40. Brot FE, Bell CE, Sly WS. Purification and properties of beta-glucuronidase from human placenta. Biochemistry 1978; 17 (3): 385-91
41. Gehrmann MC, Opper M, Sedlacek HH, et al. Biochemical properties of recombinant human β-glucuronidase synthesized in baby hamster kidney cells. Biochem J 1994; 301: 821-8
42. Islam MR, Grubb JH, Sly WS. C-terminal processing of human beta-glucuronidase: the propeptide is required tor full expression of catalytic activity, intracellular retention, and proper phosphorylation. J Biol Chem 1993; 268 (30): 22627-33
43. Jain S, Drendel WB, Chen ZW, et al. Structure of human beta-glucuronidase reveals candidate lysosomal targeting and active-site motifs. Nature Structure Biol 1996; 3 (4): 375-81
44. Tanaka J, Gasa S, Sakurada K, et al. Characterization of the subunits and sugar moiety of human placental and leukemic beta-glucuronidase. Biol Chem Hoppe Seyler 1992; 373 (1): 57-62
45. Brown J, Novak EK, Takeuchi K, et al. Lumenal location of the microsomal beta-glucuronidase-egasyn complex. J Cell Biol 1987; 105 (4): 1571-8
46. Medda S, Stevens AM, Swank RT. Involvement of the esterase active site of egasyn in compartmentalization of beta-glucuronidase within the endoplasmic reticulum. Cell 1987; 50 (2): 301-10
47. Zhen LD, Baumann H, Novak EK, et al. The signal for retention of the egasyn-glucuronidase complex within the endoplasmic reticulum. Arch Biochem Biophys 1993; 304 (2): 402-14
48. De Duve C, Pressman C, Gianetto R, et al. Tissue franctionation studies: intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J 1955; 60: 604-17
49. Fishman WH, Goldman SS, DeLellis R. Dual localization of β-glucuronidase in endoplasmic reticulum and in lysosomes. Nature 1967; 213: 457-60
50. Tomino S, Paigen K. Egasyn, a protein complexed with microsonial β-glucuronidase. J Biol Chem 1975; 250 (3): 1146-8
51. Catterall JF, Leary SL. Detection of early changes in androgen-induced mouse renal beta-glucuronidase messenger ribonucleic acid using cloned complementary deoxyribonucleic acid. Biochemistry 1983; 22 (26): 6049-53
52. Palmer R, Gallagher PM, Boyko WL, et al. Genetic control of levels of murine kidney glucuronidase mRNA in response to androgen. Proc Natl Acad Sci USA 1983; 80: 7596-600
53. Bracey LT, Paigen K. Changes in translational yield regulate tissue-specific expression of beta-glucuronidase. Proc Natl Acad Sci USA 1987; 84 (24): 9020-4
54. Sokolove PM, Wilcox MA, Thurman RG, et al. Stimulation of hepatic microsomal β-glucuronidase by calcium. Biochem Biophys Res Commun 1984; 121 (3): 987-93
55. Schöllhammer I, Poll DS, Bickel MH. Liver microsomal beta-glucuronidase and UDP-glucuronosyltransferase. Enzyme 1975; 20: 269-76
56. Szasz G. Die Bestimmung der β-Glucuronidase Aktivität im Serum mit p-Nitrophenyl-glucuronid. Clin Chim Acta 1967; 15: 275-82
57. Lusis AJ, Tomino S, Paigen K. Isolation, characterization, and radioimmunoassay of murine egasyn, a protein stabilizing glucuronidase membrane binding. J Biol Chem 1976; 251 (24): 7753-60
58. Sperker B, Schick M, Kroemer HK. High-performance liquid chromatographic quantification of 4-methylumbelliferyl-β-D-glucuronide as a probe for human β-glucuronidase activity in tissue homogenates. J Chromatogr B 1996; 685: 181-4
59. Fishman WH, Baker JR. Cellular localization of β-glucuronidase in benign and malignant tissue. J Histochem Cytochem 1956; 4: 412-4
60. Hayashi M, Nakajima Y, Fishman WH. The cytologic demonstration of β-glucuronidase employing naphtol AS-BI glucuronide and hexazonium pararosanilin; a preliminary report. J Histochem Cytochem 1964; 12: 293-7
61. Jefferson RA. Assaying chimeric genes in plants: the GUS gene fusion protein. Plant Mol Biol Reporter 1987; 5 (4): 387-405
62. Sperker B, Mürdter TE, Fritz P, et al. 'Phase III'-drug metabolism in man: characterization of enzyme-substrate interactions of human-glucuronidase [abstract]. Exp Toxicol Pathol 1996; 48 (5): 392
63. Brown RT, Carter NE, Scheinmann F, et al. Synthesis of morphine-6-glucuronide via a highly selective enzyme catalysed hydrolysis reaction. Tetrahedron Lett 1995; 36 (7): 1117-20
64. Dickinson RG, King AR. Studies on the reactivity of aycl glucuronides. V. Glucuronide-derived covalent binding of diflunisal to bladder tissue of rats and its modulation by urinary pH and β-glucuronidase. Biochem Pharmacol 1993; 46 (7): 1175-82
65. Narita M, Nagai E, Hagiwara H, et al. Inhibition of beta-glucuronidase by natural glucuronides of kampo medicines using glucuronide of SN-38(7-ethyl-10-hydroxycamptothecin) as a substrate. Xenobiotica 1993; 23 (1): 5-10
66. Gesson J-P, Jacquesy J-C, Mondon M, et al. Prodrugs of anthracyclines for chemotherapy via enzyme-monoclonal antibody conjugates. Anticancer Drug Des 1994; 9: 409-23
67. Haisma HJ, Boven E, van Muijen M, et al. A monoclonal antibody-beta-glucuronidase conjugate as activator of the prodrug epirubicin-glucuronide for specific treatment of cancer. Br J Cancer 1992; 66 (3): 474-8
68. Azoulay M, Florent JC, Monneret C, et al. Prodrugs of anthracycline antibiotics suited for tumor-specific activation. Anticancer Drug Des 1995; 10: 441-50
69. Kauffman FC. Regulation of drug conjugate production by futile cycling in intact cells. In: Kauffman FC, editor. Conjugation-deconjugation reactions in drug metabolism and toxicity. New York: Springer, 1994: 245-55
70. Hansel SB, Morris ME. Hepatic conjugation/deconjugation cycling pathways. Computer simulations examining the effect of Michaelis-Menten parameters, enzyme distribution patterns, and a diffusional barrier on metabolite disposition. J Pharmacokinet Biopharm 1996; 24 (2): 219-43
71. Arnoux B, Joseph M, Simoes MH, et al. Antigenic release of paf-acether and β-glucuronidase from alveolar macrophages of asthmatics. Bull Eur Physiopathol Respir 1987; 23: 119-24
72. Ho KJ, Hsu SC, Chen JS, et al. Human biliary beta-glucuronidase: correlation of its activity with deconjugation of bilirubin in the bile. Eur J Clin Invest 1986; 16 (5): 361-7
73. Whiting JF, Narciso JP, Chapman V, et al. Deconjugation of bilirubin-IX glucuronides: a physiologic role of hepatic microsomal-glucuronidase. J Biol Chem 1993; 268 (31): 23197-201
74. Sirota L, Ferrera M, Lerer N, et al. Beta glucuronidase and hyperbilirubinaemia in breast fed infants of diabetic mothers. Arch Dis Child 1992; 67 (1): 120-1
75. Rollins DE, Klaassen CD. Biliary excretion of drugs in man. Clin Pharmacokinet 1979; 4: 368-79
76. Caldwell JH, Greenberger NJ. Interruption of the enterohepatic circulation of digitoxin by cholestyramine. J Clin Invest 1971; 50: 2626-37
77. Herman RJ, van Pham JD, Szakacs CBN. Disposition of lorazepam in human beings: enterohepatic recirculalion and first-pass effect. Clin Pharmacol Ther 1989; 46: 18-25
78. Plaa GL. The enterohepatic circulation. In: Gillette JR, Mitchell JR, editors. Handbook of experimental pharmacology (28 Pt 3). New York: Springer, 1975: 130-49
79. Marselos M, Dutton G, Hänninen O. Evidence that D-glucaro-1,4-lactone shortens the pharmacological action of drugs being disposed via the bile as glucuronides. Biochem Pharmacol 1975; 24: 1855-8
80. Gugler R, Kürten JW, Jensen CJ, et al. Clofibrale disposition in renal failure and acute and chronic liver disease. Eur J Clin Pharmacol 1979; 15: 341-7
81. Rowe BJ, Meffin PJ. Diisopropylfluorophosphate increases clofibric acid clearance: supporting evidence for a futile cycle. J Pharmacol Exp Ther 1984; 230 (1): 237-41
82. Smith PC, McDonagh AF, Benet LZ. Effect of esterase inhibition on the disposition of zomepirac glucuronide and its covalent binding to plasma proteins in the guinea pig. J Pharmacol Exp Ther 1990; 252 (1): 218-24
83. Brunelle FM, Verbeeck RK. Glucuronidation of diflunisal by rat liver microsomes: effect of microsomal β-glucuronidase activity. Biochem Pharmacol 1993; 46 (11): 1953-8
84. Abe N, Ebina T, Ishida N. Interferon induction by glycyrrhizin and glycyrrhetinic acid in mice. Microbiol Immunol 1982; 26 (6): 535-6
85. Kumagai A, Yano M, Otomo M, et al. Study on the corticoid-like action of glycyrrhizin and mechanism of its action. Endocrinol Jpn 1957; 4: 17-27
86. Pompei R, Flore O, Marccialis MA, et al. Glycyrrhizic acid inhibits virus growth and inactivates virus particles. Nature 1979; 281: 689-90
87. Farese Jr RV, Biglieri EG, Shackleton CHL, et al. Licorice-induced hypermineralocorticoidism. N Engl J Med 1991; 325: 1223-7
88. Akao T, Akao T, Hattori M, et al. Hydrolysis of glycyrrhizin to 18 beta-glycyrrhetyl monoglucuronide by lysosomal beta-D-glucuronidase of animal livers. Biochem Pharmacol 1991; 41 (6-7): 1025-9
89. Kanaoka M, Yano S, Kato H, et al. Synthesis and separation of 18-glycyrrhetyl monoglucuronide from serum of a patient with glycyrrhizin-induced pseudo-aldosteronism. Chem Pharm Bull 1986; 34 (12): 4978-83
90. Takasuna K, Kasai Y, Kitano Y, et al. Protective effects of kampo medicines and baicalin against intestinal toxicity of a new anticancer camptothecin derivative, irinotectan hydrochloride (CPT-11), in rats. Jpn J Cancer Res 1995; 86: 978-84
91. Kari FW, Kauffman FC, Thurman RG. Effect of bile salts on rates of formation, accumulation, and export of mutagenic metabolites from benzo(a)pyrene produced by the perfused rat liver. Cancer Res 1985; 45: 1621-7
92. Whittaker M, Sokolove PM, Thurman RG, et al. Stimulation of 3-benzo[a]pyrenyl glucuronide hydrolysis by calcium activation of microsomal beta-glucuronidase. Cancer Lett 1985; 26: 145-52
93. Kinoshita N, Gelboin HV. Beta-glucuronidase catalyzed hydrolysis of benzo[a]pyrene-3-glucuronide and binding to DNA. Science 1978; 199: 307-9
94. Walaszek Z. Potential use of D-glucaric acid derivatives in cancer prevention. Cancer Lett 1990; 54 (1-2): 1-8
95. Walaszek Z, Hanausek-Walaszek M, Webb TE. Inhibition of 7,12-dimethylbenzynthracene-induced rat mammary tumorigenesis by 2,5-di-O-acetyl-D-glucaro-1,4: 6,3-dilactone, an in vivo beta-glucuronidase inhibitor. Carcinogenesis 1984; 5 (6): 767-72
96. Tsuruoka T, Fukuyasu H, Ishii M, et al. Inhibition of mouse tumor metastasis with nojirimycin-related compounds. J Antibiol 1996; 49 (2): 155-61
97. Levvy GA. The preparation and properties of beta-glucuronidase. Biochemistry 1952; 52: 464-72
98. Young JC, Kenyon EM, Calabrese EJ. Inhibition of beta-glucuronidase in human urine by ascorbic acid. Hum Exp Toxicol 1990; 9 (3): 165-70
99. Schmeda-Hirschmann G, Loyola JI, Reyes S, et al. β-Glucuronidase inhibition and diuretic activity of Fabiana imbricata r & p (solanaceae). Phytother Res 1994; 8 (8): 485-7
100. Chang HW, Friedman ME, Hileman DL, et al. Inhibition of human synovial beta-glucuronidase by steroidal compounds [short communication]. J Enzym Inhib 1993; 6 (4): 331-5
101. Satoh T, Nishimura Y, Kondo S, et al. Synthesis and antimetastatic activity of 6-trichloroacetamido and 6-guanidino analogues of siastatin B. J Antibiot 1996; 49 (3): 321-5
102. Igarashi Y, Ichikawa M, Ichikawa Y. Synthesis of a potent inhibitor of beta-glucuronidase. Tetrahedron Lett 1996; 37 (16): 2707-8
103. Nishimura Y, Satoh T, Adachi H, et al. The first L-iduronic acid-type 1-N-iminosugars having inhibitory activity of experimental metastasis. J Am Chem Soc 1996; 118 (12): 3051-2
104. Melton RG, Sherwood R. Antibody-enzyme conjugates for cancer therapy. J Natl Cancer Inst 1996; 88 (3/4): 153-65
105. Blakey DC, Burke PJ, Davies DH, et al. Antibody-directed enzyme prodrug therapy (ADEPT) for treatment of major solid tumour disease. Ther Monoclonals 1995; 23: 1047-50
106. Bagshawe KD, Springer CJ, Searle F, et al. A cytotoxic agent can be generated selectively at cancer sites. Br J Cancer 1988; 58: 700-3
107. Bagshawe KD. Antibody-directed enzyme prodrug therapy. Clin Pharmacokinet 1994; 27: 368-76
108. Sharma SK, Bagshawe KD, Melton RG, et al. Human immune response to monoclonal antibody-enzyme conjugates in ADEPT pilot clinical trial. Cell Biophys 1992; 21: 109-20
109. Bosslet K, Czech J, Lorenz P, et al. Molecular and functional characterisation of a fusion protein suited for tumour specific prodrug activation. Br J Cancer 1992; 65 (2): 234-8
110. Leenders RGG, Scheeren HW, Houba PHJ, et al. Synthesis and evaluation of novel daunomycin-phosphate-sulfate-beta-glucuronide and beta-glucoside prodrugs for application in ADEPT. Bioorg Med Chem Lett 1995; 5 (24): 2975-80
111. Wang SM, Chern JW, Yeh MY, et al. Specific activation of glucuronide prodrugs by antibody-targeted enzyme conjugates for cancer therapy. Cancer Res 1992; 52 (16): 4484-91
112. Mürdter TE, Sperker B, Kivistö KT, et al. Enhanced uptake of doxorubicin into bronchial carcinoma: β-glucuronidase mediates release of doxorubicin from a glucuronide prodrug (HMR 1826) at the tumor site. Cancer Res 1997; 57: 2440-5
113. Martin GR, Jain RK. Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. Cancer Res 1994; 54: 5670-4
114. Ashby BS. pH studies in human malignant tumours. Lancet 1966; II: 312-5
115. Jähde E, Rajewsky MF. Tumor-selective modification of cellular microenvironment in vivo: effect of glucose infusion on the pH in normal and malignant rat tissues. Cancer Res 1982; 42: 1505-12
116. Fishman WH, Anlyan AJ. The presence of high β-glucuronidase activity in cancer tissue [letter]. J Biol Chem 1947; 169: 449-50
117. Anghileri LJ, Miller ES. β-glucuronidase activity in tumors. Accumulation of radioiodinated phenolphthalein. Oncology 1971; 25: 19-32
118. Fishman WH, Baker JR, Borges PRF. Localization of β-glucuronidase in some human tumors. Cancer 1959; 12: 240-5
119. Young CW, Yagoda A, Bittar ES, et al. Therapeutic trial of aniline mustard in patients with advanced cancer: comparison of therapeutic response with cytochemical assessment of tumor cell beta-glucuronidase activity. Cancer 1976; 38: 1887-95
120. Connors TA, Whisson ME. Cure of mice bearing advanced plasma cell tumours with aniline mustard: the relationship between glucuronidase activity and tumour sensitivity. Nature 1966; 210: 866-7
121. Connors TA, Farmer PB, Foster AB, et al. Metabolism of aniline mustard [N′,N-di-(2-chloroethyl)aniline]. Biochem Pharmacol 1973; 22: 1971-80
122. Double JA, Workman P. A new high-glucuronidase mouse tumor curable by aniline mustard therapy. Cancer Treat Rep 1977; 61 (5): 909-11
123. Bosslet K, Czech J, Hoffmann D. A novel one-step tumor-selective prodrug activation system. Tumor Targeting 1995; 1: 45-50