Japanese monkey (Macaca fuscata) with alveolar echinococcosis after treatment with albendazole for 10 years: serodiagnosis and determination of albendazole metabolites.

In 1997, an outbreak of alveolar echinococcosis in Japanese monkeys (Macaca fuscata) occurred in a zoo in Hokkaido, Japan. Twelve infected monkeys from a colony (n = 57) were diagnosed serologically by Western blotting, and ultrasonography showed the presence of tumor-like tissue in the livers of nine monkeys. The 12 infected monkeys have been treated with albendazole for 10 years without surgical resection. Ten of these monkeys have died so far; diagnoses were confirmed histopathologically through autopsy. Two of these monkeys are still alive. Recently, a significant difference between the two living monkeys was recognized. A difference in curative effect was demonstrated between the two living monkeys by radiography, contrast enhanced computed tomography, and contrast ultrasound. One showed metastasis to various organs, and the other appeared to be almost cured, as demonstrated by size reduction and calcification of the lesion after albendazole treatment for 10 years. This time, serological reexamination was performed to corroborate this apparent difference. The serological tests supported the preliminary imaging findings. In addition, the presence of albendazole metabolites in sera was confirmed by high-performance liquid chromatography. In this study, it was demonstrated that tests which have been used in human cases were also effective for diagnosing alveolar echinococcosis and for assessing curative effects in nonhuman primates such as M. fuscata.

Intracellular conversion of irinotecan to its active form, SN-38, by native carboxylesterase in human non-small cell lung cancer.

The anticancer agent irinotecan (CPT-11) is a prodrug converted to its active form, SN-38, by human carboxylesterase (hCE) and the SN-38 is further metabolized to its inactive form, SN-38G. We investigated the expression of hCE in human lung cancer cells as well as the ability of these cells to convert CPT-11 to SN-38 using surgically resected tumor samples and cultured cell lines. SN-38 was 40- to 3,000-fold more toxic to lung cancer cell lines than CPT-11, which acted more time-dependently than SN-38. Although human lung cancer cells expressed hCE in the cytoplasm, hCE expression levels in cancer cells were not correlated with their drug sensitivities. Although intracellular CPT-11 and SN-38 levels continuously increased within 60 min of CPT-11 exposure, SN-38 levels in cells exposed to SN-38 decreased. Cells with the ability to metabolize SN-38 to SN-38G were more resistant to extracellular SN-38 than cells lacking the ability. Of 25 squamous cell carcinomas, 15 were strongly positive for hCE and six were negative. Of 25 adenocarcinomas, four were strongly positive for hCE and 16 were positive, while five were negative. Thus, 70% of non-small cell lung cancers expressed hCE. From these results, we conclude that human lung cancer cells expressed the enzyme which can convert CPT-11 to SN-38 and that intracellular SN-38 converted from CPT-11 may act as a chemotherapeutic agent together with SN-38 absorbed from the outside and augment the dose intensity of SN-38. Therefore, to assess the effects of CPT-11 prior to chemotherapy, it is important to check if lung cancer cells express hCE.

Effects of a diphenyl ether-type herbicide, chlornitrofen, and its amino derivative on androgen and estrogen receptor activities.

Chlornitrofen (CNP) was widely used in large quantities as a herbicide in rice paddy fields in Japan during 1965-1994. Recently, there has been concern that chemicals in the environment may disrupt the endocrine function of wildlife and humans, but little is known about the effect of CNP on endocrine function. We have developed reporter gene assays for human androgen receptor (hAR) and human estrogen receptor-alpha (hER alpha) using Chinese hamster ovary cells. Using this assay method, we measured CNP and its amino derivative (CNP-amino) for hAR and hER alpha agonist/antagonist activities, comparing them with several well-known AR antagonists or ER agonists. We found that CNP and CNP-amino have potent antiandrogenic activities as well as estrogenic activities. The order of their antiandrogenic activity was CNP > vinclozolin > o,p-DDT = p,p-DDE > CNP-amino, and the order of their estrogenic activity was o,p-DDT > CNP-amino > p,p-DDT > CNP. We investigated the binding ability of CNP and CNP-amino to hAR and hER alpha using a receptor competitive-binding assay. The order of their binding potencies to hAR was CNP > o,p-DDT = p,p-DDE = CNP-amino > vinclozolin, and that of their binding potencies to hER alpha was o,p-DDT > CNP-amino > p,p-DDT = CNP. These results suggest that both CNP and CNP-amino may act as endocrine disruptors via AR and ER alpha in humans and other animals. Our reporter gene assays are highly sensitive and specific and are suitable for screening AR and ER alpha agonist/antagonists among numerous environmental chemicals.