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Abstract Acute Emetic Responses to Seven Cancer Chemotherapeutic Emesis Induced by Cancer Chemotherapeutic Agents in the Suncus Murinus: A New Experimental Model Norio MATSUKI, Shinya UENO, Takahide KAJI, Akane ISHIHARA, Chao-Hsiung WANG k and Hiroshi SAITO Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan Chia-nan Junior College of Pharmacy, Tainan Hsien, Taiwan Accepted September 1, 1988 Abstract Acute emetic responses to seven cancer chemotherapeutic agents (adriamycin, bleomycin, cisplatin, cyclophosphamide, 5-fluorouracil, methotrexate, mitomycin C) were studied in the Suncus murinus. Intravenous injection of the drugs caused vomiting with various latency. Cisplatin-induced emesis was prevented by the pretreatment with metoclopramide or chlorpromazine but not with domperidone. These results indicate that the Suncus murinus is a useful animal for testing emetic activities of cancer chemotherapeutics and antiemetic activities of prophylactic drugs. Nausea and vomiting, although rarely life threatening, are painful side effects for the patients who receive cancer chemotherapy (1). However, developments of less emetic chemotherapeutic agents and antiemetic drugs are difficult because only a few mammals vomit in response to emetic drugs. The smallest mammal currently available for these purposes is the ferret (2,3), but its body weight is more than 1 kg. If we could use smaller mammals, it would be easier to test various agents for emetic and antiemetic activities. Recently we have shown that the Suncus murinus (house musk shrew), a species of insectivora, vomit in response to various emetic drugs (4) or motion stimulus (5). However, it is not known whether cancer chemotherapeutics induce emesis in the suncus. In the present study emetic response to several chemotherapeutics were investigated in the suncus for its use as a new animal model for emesis testing. Healthy adult Suncus murinus of either sex weighing 50-80 g (male) and 30-50 g emale were used. The animals, originally introduced from the Central Institute for Experimental Animals (Kanagawa, Japan), were bred in animal care facilities in University of Tokyo. When effects of drugs were studied, each animal was placed in a transparent cage and allowed 10 min to accustom to the new circumstances. Cancer chemotherapeutic agents were injected into jugular vein under light ether anesthesia. The anesthetizing effect of ether was disappeared within 5 min. The number of vomiting episodes and the time from the intravenous injection of drugs to the first vomiting episode (latency) were recorded for 90 min. Cancer chemotherapeutic agents used in the present study were as follows: adriamycin (Sigma), bleomycin (Nihon Kayaku), cisplatin (Sigma), cyclophosphamide (Shionogi), 5 fluorouracil (Mitsui), methotrexate (Lederle), mitomycin C (Kyowa Hakko). Emetic effects of seven chemotherapeutics are summarized in Table 1. All drugs tested induced vomiting. The doses of the drugs were determined in preliminary experiment. A small dose of drugs, usually one tenth to half of reported LD50 values in mice or rats, was injected into one or two animals. The dose was increased stepwise until emesis or fatal toxicity was observed. Results obtained from three or more suncus were listed in the table. No animal died during 90 minutes' observation period. There was no apparent drug-dependent difference in total number of vomiting episodes. However, the latency to the first vomiting induced by cisplatin and 5-fluorouracil was definitely longer. Therefore, it is possible either that metabolites rather than original compounds cause emesis or slow process is involved before vomiting center is finally stimulated. Long latency of cisplatin induced emesis is also reported in case of ferret (2,3) and cat (6). Although we did not check all of the suncus studied, no vomiting was observed after 90 minutes' observation period. The latest emesis was occurred 62 min after the injection of 40 mg/kg cisplatin. Cisplatin, one of chemotherapeutic agents which cause high incidence of emesis (7), induced constant vomiting in the suncus. Metoclopramide and domperidone are used as antiemetic drugs during various cancer chemotherapy. Therefore, effects of these drugs against cisplatin-induced emesis were studied. Effects of 32 mg/kg chlorpromazine (Sigma) which completely blocked the emesis induced by veratrine, nicotine, copper sulfate (4) and motion stimulus (5) in the suncus were also studied for comparison. Antiemetic drugs were injected subcutaneously 30 min prior to the intravenous injection of 40 mg/kg cisplatin. As shown in Table 2, Table 1 Emetic effects of seven cancer chemotherapeutic agents in suncus Table 2 Effects of domperidone, metoclopramide and chlorpromazine on cisplatin-induced emetic responses in suncus domperidone (Kyowa Hakko) was not effective but 100 mg/kg metoclopramide (Fujisawa) completely prevented the cisplatin induced emesis. Domperidone did not affect the latency but tended to increase number of vomiting episodes caused by cisplatin. Three out of five animals treated with 10 mg/kg domperidone died after the injection of cisplatin but only one animal died when the dose of domperidone was increased to 100 mg/kg. We do not know the reason why 10 mg/kg domperidone was more toxic. Chlorpromazine was very effective and completely blocked the emesis. The doses of cancer chemotherapeutic agents which induced emesis in suncus were higher than previously reported doses in cat, dog and ferret. Cisplatin at a dose of 3 to 10 mg/kg induced frequent emesis, and low doses of 2 to 6 mg/kg metoclopramide attenuated emetic effect of cisplatin and delayed the onset in these animals (2,3,6,8,9). Therefore, sensitivities of the suncus to emetic and antiemetic drugs may be low compared to other experimental animals. However, all of seven cancer chemothera peutic agents induced emesis at doses smaller than acute lethal doses, and metoclopramide prevented it in the suncus. As far as the authors can concern, the suncus is the smallest mammal which vomits in response to chemotherapeutics. Using small animals for screening of drugs has several advantages. Emetic effects of a great variety of drugs can be tested within a short period of time. There are probably several input pathways which finally lead to emetic response, and species differences in sensitivities to emetic and antiemetic drugs are well known (10). Therefore, further studies are necessary to characterize the emetic response in the suncus and to elucidate interspecies differences. In conclusion, the present results suggest that we can use the Suncus murinus as a new animal model for testing emetic activities of cancer chemotherapeutics and antiemetic activities of prophylactic drugs. REFERENCES 1 Coates,A., Abraham,S., Kaye,S.B., Sowerbutts,T., Frewin,C., Fox,R.M. and Tattersall,M.H.N.: On the receiving end-patient perception of the side-effects of cancer chemotherapy. Eur.J.Cancer Clin.Oncol. 19, 203-208 (1983) 2 Florczyk,A.P., Schurig,J.E. and Bradner,W.T.: Cisplatin-induced emesis in the ferret: A new animal model. Cancer Treat.Rep. 66, 187-189 (1982) 3 Costall,B., Domeney,A.M., Naylor,R.J. and Tattersall,F.D.: Emesis induced by cisplatin in the ferret as a model for the detection of anti-emetic drugs. Neuropharmacol. 26, 1321-1;326 (1987) 4 Ueno,S., Matsuki,N. and Saito,H.: Suncus murinus: A new exper imental model in emesis research. LiFe-Sci. 41, 513-518 (1987) 5 Ueno,S., Matsuki,N. and Saito,H.: Suncus murinus as a new experimental model for motion sickness. Life ci. 43, 413-420 (1988) 6 McCarthy,L.E. and Borison,H.L.: Cisplatin-induced vomiting eliminated by ablation of the area postrema in cats. Cancer Treat.Rep. 68, 401-404 (1984) 7 Gralla,R.J., Tyson,L.B., Bordin,L.A., Clark,R.A., Kelsen,D.P., Kris,M.G., Kalman,L.B. and Groshen,S.: Antiemetic therapy: A review of recent studies and a report of a random assignment trial comparing metoclopramide with delta-9-tetrahydro cannabinol. Cancer Treat.Rep. 68, 163-172 (1984) 8 Alphin,R.S., Proakis,A.G., Leonard,C.A., Smith,W.L., Dannenburg,W.N., Kinnier,W.J., Johnson,D.N., Sancilio,L.F. and Ward,J.W.: Antagonism of cisplatin-induced emesis by metoclopramide and dazopride through enhancement of gastric motility. Digest.Dis.Sci. 31, 524-529 (1986) 9 Costall,B., Domeney,A.M., Naylor,R.J. and Tattersall,F.D.: 5 Hydroxytryptamine M-receptor antagonism to prevent cisplatin induced emesis. Neuropharmacol. 25, 959-961 (1986) 10 Borison,H.L. and Wang,S.C.: Physiology and pharmacology of vomiting. Pharmacol.Rev. 5, 193-230 (1953) .
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