TZT-1027, a dolastatin 10 derivative, is an antimicrotubule agent with potent antitumor activity both in vitro and in vivo. In this study, we performed biochemical and histopathological examinations, and evaluated TZT-1027-induced tumoral vascular collapse and tumor cell death in an advanced tumor model, murine colon 26 adenocarcinoma. In addition, we studied the effects of TZT-1027 on cultured human umbilical vein endothelial cells (HUVEC). Tolerable doses of TZT-1027 induced tumor-selective hemorrhage within 1 h. This hemorrhage occurred mainly in the peripheral area of the tumor mass. Measurements of tumoral hemoglobin content and dye permeation revealed that the hemorrhage occurred firstly and tumor blood flow stopped secondarily. The vascular damage was followed by continuous induction of apoptosis of the tumor cells, tumor tissue necrosis, and tumor regression. In cultured HUVEC, TZT-1027 induced marked cell contraction with membrane blebbing in 30 min. These cell changes were completely inhibited by K252a, a broad-spectrum inhibitor of protein kinases. These effects of TZT-1027 on both tumor vasculature and HUVEC were greater than those of vincristine. In conclusion, TZT-1027 quickly attacked the well-developed vascular system of advanced tumors by a putative protein kinase-dependent mechanism, and then blocked tumor blood flow. Therefore, TZT-1027 has both a conventional antitumor activity and a unique anti-tumoral vascular activity, making it a potentially powerful tool for clinical cancer therapy.
The effect of a synthetic steroidal anti‐androgen, TZP‐4238, on spontaneous benign prostatic hyperplasia (BPH) in dogs was investigated. Old male beagle dogs (5–9 years old) were divided into three experimental groups. Group 1 consisted of BPH controls. Groups 2 and 3 received TZP‐4238 0.1 mg/kg/day and chlormadinone acetate (CMA) 0.3 mg/kg/day P.o., respectively, for 5 months. In group 1, glandular hyperplasia of the prostate was clearly detected. In contrast, TZP‐4238 (Group 2) or CMA (Group 3) produced marked atrophy of the glandular epithelium. In addition, a histopathological study showed that TZP‐4238 or CMA medication for 5 months exerted no effect on the testes and the pituitary luteinizing hormone (LH) cells. Therefore, it is suggested that TZP 4238 (0.1 mg/kg) or CMA (0.3 mg/kg) causes regression of spontaneous canine BPH without any histopathological effects on the testes and pituitary LH cells. However, slightly decreased serum testosterone levels were found in TZP 4238 treated animals, due apparently to a direct and/or indirect effect on the testes. Thus, it is suggested that a marginal antigonadotrophic effect cannot be excluded. It is concluded that TZP‐4238 is a potent anti‐androgen for the treatment of spontaneous canine BPH, without any negative influence on the function of the testes and the pituitary LH cells. Acta Pathol Jpn 42: 151–157, 1992.
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