Hirotaka Chikazawa

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.

Schedule-dependent and -independent Antitumor Activity of Paclitaxel-based Combination Chemotherapy against M-109 Murine Lung Carcinoma in vivo

The established antitumor efficacy of paclitaxel against a variety of human tumors has led to pre‐clinical and clinical studies to develop the paclitaxel‐based combination regimens. We examined in vivo the antitumor activity and toxicity of the combination of paclitaxel and each of 8 antitumor agents, currently in clinical use, against M‐109 murine lung carcinoma implanted subcutaneously into male CDF1 mice. Paclitaxel given intravenously at 24 mg/kg/day on a schedule of consecutive daily injections for 5 days (d1–5) induced reproducibly, in 6 experiments, a significant (37–82%) increase in the survival time of tumor‐bearing mice over saline‐treated control mice. Cisplatin at 4 and 2 mg/kg/day given intravenously on the same treatment schedule showed no significant antitumor activity when given alone; however, the combination of paclitaxel at 24 mg/kg/day (d1–5) followed by cisplatin at a dose of 2 mg/kg/day (d6–10) induced a significant (P<0.05) prolongation of the survival time of tumor‐bearing mice compared with the group given paclitaxel alone. On the other hand, treatment with these drugs on the reverse sequence caused toxic deaths of all mice. Such sequence‐dependent toxic death of mice was also observed with the combination of paclitaxel and carboplatin, etoposide or methotrexate. The combination of paclitaxel and adriamycin, cyclophosphamide, ranimustine or vinblastine (VLB) showed a sequence‐independent antitumor activity and a more‐than‐additive therapeutic effect was observed with the combination of paclitaxel and either VLB or ranimustine. Although the drug administration schedules used here may not be directly applicable to the clinic, knowledge of the nature of the sequence‐dependency in paclitaxel‐based combination chemotherapy should be useful in the design of clinical trials.