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Effects of a CDK9 inhibitor RKP00156 on bovine papilloma
Acosta, T.J.; Onogi, H.
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Bovine papilloma virus (BPV) induces diseases of considerable veterinary importance in cattle and other ruminants. BPV infects the skin from wounds such as puncture scratches by bloodsucking insects. Papilloma grows as tumor at the site of infection, papilloma located on the teats and udder skin are often observed and it is associated with mastitis in dairy cows. Several genotypes of BPV was recently divided into three genera, Delta, Xi, and Epsilon. It is difficult to identify the virus type based on the gross characteristics of tumor located on skin. In most cases, animals are co-infected by multiple genotypes. An efficient treatment method for papilloma has not been established. Recently, a cyclin-dependent kinase 9 (CDK9) inhibitor RKP00156 that inhibit host enzymes used by the virus, was shown to be effective against a wide range of viruses in vitro and cold be used as an antiviral drug. The purpose of this study was to examine the effect of RKP00156 on papilloma and BPV expression in cattle.
Ten Holstein heifers (16 to 20 months), infected with papilloma virus were used in the present study. The left anterior teat of each animal was assigned to treatment group (T group) and the right anterior teat was used as control group (C group). RKP00156 (3%) ointment was topically applied to the teat (T group) and Vaseline ointment (vehicle) was applied to C group once a day for 2 months. Before each application, pictures of each teat was taken to evaluate the changes in the tumor size and the fate of tumors at fourth week (W4) and eight week (W8) after the start of treatment (W0), tumors samples were also collected for PCR analysis after DNA extraction. Genotype identification and virus expressions were evaluated on W4 and W8 in tissue samples. The changes in size and fate of papilloma was evaluated from the pictures, and the tumors were classified in three categories (improved; decreased in size or disappeared, no change; kept the same size, and worse; increased in size or appeared during the experiment). The differences in the size and fate of tumors between treatment and control groups were compared and analyzed by Fisher's exact test.
On W4, the improved rate of papilloma was higher and the worse rate was lower in T group than in C group (P <0.1). Furthermore, on W8, the improved rate of T group further increased and the worse rate decreased. PCR analysis performed on W4 revealed that Delta and Xi types of BPV were expressed in the same number of teats in both groups, however, on W8, the number of teats expressing Delta and Xi decreased significantly compared with that of controls. These results indicate that administration of CDK 9 inhibitor RKP00156 ameliorated papilloma formation and reduced BPV expression, suggesting that RKP00156 has a good potential to be used as antiviral agent for papilloma treatment in cattle.
Keywords: Papillomatosis, bovine papilloma virus, CDK9 inhibitor.
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Affiliation of the authors at the time of publication
Obihiro University, Obihiro, Japan;
KinoPharma Inc., Tokyo, Japan.
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