Toshihito Kadota

Anti-tumor Efficacy of Paclitaxel against Human Lung Cancer Xenografts

We examined paclitaxel for anti‐tumor activity against human lung cancer xenografts in nude mice and compared its efficacy with that of cisplatin, currently a key drug for lung cancer chemotherapy. Five non‐small cell lung cancers (A549, NCI‐H23, NCI‐H226, NCI‐H460 and NCI‐H522) and 2 small cell lung cancers (DMS114 and DMS273) were chosen for this study, since these cell lines have been well characterized as regards in vitro and in vivo drug sensitivity. These cells were exposed to graded concentrations of paclitaxel (0.1 to 1000 nM) for 48 h. The 50% growth‐inhibitory concentrations (GI50) for the cell lines ranged from 4 to 24 nM, which are much lower than the achievable peak plasma concentration of paclitaxel. In the in vivo study, 4 cell lines (A549, NCI‐H23, NCI‐H460, DMS‐273) were grown as subcutaneous tumor xenografts in nude mice. Paclitaxel was given intravenously as consecutive daily injections for 5 days at the doses of 24 and 12 mg/kg/day. Against every xenograft, paclitaxel produced a statistically significant tumor growth inhibition compared to the saline control. Paclitaxel at 24 mg/kg/day was more effective than cisplatin at 3 mg/kg/day with the same dosing schedule as above, although the toxicity of paclitaxel was similar to or rather lower than that of cisplatin, in terms of body weight loss. In addition, paclitaxel showed potent activity against 2 other lung cancer xenografts (NCI‐H226 and DMS114). Therefore, paclitaxel showed more effective, wider‐spectrum anti‐tumor activity than cisplatin in this panel of 6 lung cancer xenografts. These findings support the potential utility of paclitaxel in the treatment of human lung cancer

Toxicological study of etoposide (VP-16) in rats with special emphasis on testicular alteration.

Etoposide (VP-16) was administered intravenously to rats for 3 months. Testicular alterations induced by etoposide (VP-16) at 0.5 and 1.5 mg/kg/d were thoroughly assessed with light and electron microscopy. Light microscopic analyses demonstrated disorganization and moderate depletion of germinal epithelium at 0.5 mg/kg/d, and complete germ cell depopulation at 1.5 mg/kg/d. Ultrastructural studies revealed degenerative changes in spermatogonia and early spermatocytes, appearance of large spermatids with multi-nuclei, and nuclear alterations and cytoplasmic vacuolation in Sertoli cells. Moreover, the basement membrane of the seminiferous tubule showed wavy lamellae and infolding to the seminiferous epithelium. Leydig cells manifested no significant ultrastructural changes. The small intestine and ovaries were not affected. The 2-month recovery period following cessation of treatment led to the recovery of these testicular alterations at the 0.5 mg/kg/d dose, but not at the 1.5 mg/kg/d dose. Judging from these results, etoposide (VP-16) induced damage primarily in spermatogenic cells, followed by Sertoli cells and the basement membrane in seminiferous tubules. Though reversible at intermediate doses, higher doses of VP-16 might produce irreversible testicular lesions.

Spontaneous Basal Cell Carcinoma of the Submandibular Gland in a Rat

At necropsy, a white nodule (about 5 × 3 mm in size) was observed in the right submandibular gland of a 10-week-old female GALAS rat. Histopathologically, oval to spindle-shaped and pale basophilic tumor cells proliferated closely, and formed variably sized foci. The nodule partially spread into or invaded the surrounding normal tissue, and necrotic foci were recognized in the tumor. Immunohistochemically, the nuclei of the tumor cells showed a diffusely positive reaction for p63, and the cytoplasm showed a diffusely positive reaction for cytokeratin and negative reaction for αSMA, vimentin, desmin and S-100. Many tumor cells were positive for PCNA. Ultrastructurally, the tumor cells contained many tonofilaments in the cytoplasm and a few desmosomes at the intercellular portion. Based on these findings, the tumor was diagnosed as a basal cell carcinoma originating from the duct in the rat submandibular gland.