[Study on the combined therapy of DNA-methyltransferase inhibitor and interferon-alpha/beta for mouse spontaneously arose renal cell carcinoma, and immunological mechanism induced by the therapy].
BACKGROUND
In order to change the immunological environment of T-helper2 (Th2) predominance, namely humoural immunity, in renal cell carcinoma, we tried to examine the efficacy of combined treatment with DNA-methyltransferase inhibitor (Procainamide) and interferon (IFN)-alpha/beta in basic experiments, and also examined the immunological mechanism induced by this treatment modality.


METHODS
The monotherapy of Procainamide (10 mg/kg, 20 mg/kg, 30 mg/kg, everyday for 3 weeks, i.p.) and of natural murine IFN-alpha/beta (1 x 10(4) I.U./mouse, 3 times for a week, total 9 times, s.c.), and combined treatment with these 2 drugs for mouse spontaneously arose renal cell carcinoma (RC-2) were undertaken. Furthermore, we examined the expression of cytokine mRNA related to the Th-subset in murine spleen under the tumour burden by the RT-PCR methods.


RESULTS
1) Regarding the anti-tumour efficacy of two kinds of monotherapy (Procainamide and IFN-alpha/beta), no effective result was obtained. On the other hand, the combined treatment with these two drugs induced effective anti-tumour efficacy in the relative mean tumour weight ratio (TRW/CRW), mean tumour weight and the survival rate compared with the control and each monotherapy, especially in the administration of Procainamide dosed at 30 mg/kg. As to the histological degeneration induced by the combined therapy, there still remained the viable tumour cells (grade IIb). 2) In an effort to analyse the immunological changes induced by the administration of Procainamide, there observed the expression of Th1-derived cytokines mRNA such as IFN-gamma, IL-2 and tumour necrosis factor-beta, and except for interleukin (IL)-10, there also observed the disappearance of Th2-derived cytokines mRNA such as IL-4, IL-5 and IL-6 in the murine spleen.


CONCLUSIONS
We draw the conclusion that the treatment with DNA-methyltransferase inhibitor may change the humoural immunological environment into the cellular immunological environment enabling the effective anti-tumour efficacy combined with IFN-alpha/beta in renal cell carcinoma.
Onishi
T
T
Department of Urology, Jikei University School of Medicine.
Ohishi
Y
Y
Goto
H
H
Suzuki
H
H
Asano
K
K
Hatano
T
T
Abe
K
K
Tomita
M
M
Imagawa
K
K
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology*; D015257:DNA-Cytosine Methylases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007111:Immunity, Cellular; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D011342:Procainamide / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D016899:Interferon-beta; C100787:BalI methyltransferase; D015257:DNA-Cytosine Methylases; D011342:Procainamide