Antitumoral effect of recombinant mistletoe lectin on chemically induced urinary bladder carcinogenesis in a rat model.
BACKGROUND
The objective of this study was to determine the effect of intravesically applied, recombinant, galactoside specific mistletoe lectin (rML) on chemically induced tumor development in the urinary bladder of rats.


METHODS
For tumor induction, rats were treated with four biweekly 1.5 mg doses of N-methyl-N-nitrosourea (NMU) intravesically (Weeks 0, 2, 4, and 6). The control group (n = 39 + 17 rats) received no other treatment. The four therapy groups also received rML twice weekly according to one of the following instillation regimens: 1) 30 ng rML per instillation from Week 8 to Week 13 (Group a: n = 14 rats), 2) 150 ng rML per instillation from Week 8 to Week 13 (Group b: n = 23 + 15 rats), 3) 30 ng rML per instillation from Week 14 to Week 19 (Group c: n = 22 rats), and 4) 150 ng rML per instillation from Week 14 to Week 19 (Group d: n = 19 rats). After the rats were asphyxiated at Week 21, the urinary bladders were excised in toto and examined histopathologically. To study the immunomodulatory effects of intravesically applied rML, 17 animals from the control group and 15 animals from Group b were asphyxiated at Week 13, and urinary bladder tissue was analyzed by semiquantitative reverse transcriptase-polymerase chain reaction analysis for mRNA expression of interferon-gamma, interleukin-10, and Fas ligand.


RESULTS
By Week 21, atypical hyperplasia and neoplastic transformation were found in 82% of the animals in the control group. In contrast, in all four cohorts that were treated with rML, significantly lower rates of atypical hyperplasia and neoplastic transformation were found (Group a, 50%; Group b, 52%; Group c, 45%; and Group d, 42%). By Week 13, in the bladder tissue of 15 rML-treated animals from Group b, lower expression of interleukin-10 mRNA was measured, whereas the expression levels of interferon-gamma mRNA and Fas ligand mRNA were comparable to those of 17 animals from the control group.


CONCLUSIONS
The current data provide evidence for an inhibitory effect of rML on experimental urothelial carcinogenesis that does not seem to be due to interferon-gamma and/or interleukin-10 dependent mechanisms.
Elsässer-Beile
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U
Department of Urology, Albert-Ludwigs-University, Freiburg, Germany. elsbeile@uni-freiburg.de
Ruhnau
T
T
Freudenberg
N
N
Wetterauer
U
U
Mengs
U
U
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000283:Administration, Intravesical; D000477:Alkylating Agents / Q000008:administration & dosage; D000818:Animals; D002471:Cell Transformation, Neoplastic; D005260:Female; D008770:Methylnitrosourea / Q000008:administration & dosage; D009374:Neoplasms, Experimental; D028321:Plant Preparations; D010940:Plant Proteins; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological / Q000008:administration & dosage / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019459:Urothelium / Q000187:drug effects / Q000473:pathology
D000276:Adjuvants, Immunologic; D000477:Alkylating Agents; D028321:Plant Preparations; D010940:Plant Proteins; D011994:Recombinant Proteins; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological; C009674:ribosome inactivating protein, Viscum; D008770:Methylnitrosourea