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Unlabelled: This study evaluates histological response, long-term outcome, and toxicity in an intensive chemotherapy program given before surgery., Patients and Methods: Sixty-two patients (39 males, 23 females: median age 14) with biopsy, chest computerised-tomography, technetium bone-scan and magnetic resonance imaging, were enrolled. Primary localisations were femur (44%) and tibia (26%). Induction chemotherapy involved seven courses of high-dose methotrexate and two courses of HELP (ifosfamide, eldesine (vindesine), cisplatin (platinum)-doxorubicin. After surgery, patients received six courses of high-dose methotrexate and two courses of HELP-doxorubicin., Results: Pre- and postoperative toxicities were similar. Fifty-nine patients underwent surgery; histological response was good in thirty-eight patients (64%) and poor in twenty-one (36%). Median follow-up is 57 months (range 30-80), with 77% overall survival and 59% progression-free survival. In a multivariate analysis, age under 10 years is the only prognostic factor that significantly correlates with outcome., Conclusions: This regimen appears to increase histological necrosis, but associates with severe toxicity. Results for patients with less necrosis at surgery are encouraging. Future trials should determine the minimum effective doses to reduce toxicity. New drugs should be added.

Effect of different concentrations (0, 1, 5, 10, 20 and 50 nM) of vindesine sulphate was studied on clonogenicity and micronucleus (MN) formation in V79 (Chinese hamster lung fibroblasts) cells. Exposure of V79 cells to vindesine for 6 h resulted in a concentration dependent decline in cell survival. The frequency of micronuclei (MN) increased in a concentration dependent manner at 16, 22 and 28 h post-exposure. The frequency of MN increased significantly after 5 to 50 nM drug exposure at 16 and 22 h post-treatment, while increasing post-exposure time to 28 h resulted in a significant increase in MN frequency at all exposure doses of vindesine. The statistical evaluation of concurrent concentrations at various time periods showed a non-significant difference in MN frequency among various post-exposure time periods, except 16 h and 28 h for 50 nM, where a significant decline in the MN frequency was observed at 28 h compared to 16 h post-exposure. The cell proliferation indices showed a concentration dependent decline in the frequency of binucleate cells and this decline was linear quadratic. The increasing drug concentration resulted in a concentration dependent decline in cell survival. While the frequency of micronuclei increased the cell survival decreased and the relationship between cell survival and micronucleus induction was linear quadratic., (Copyright 1998 Elsevier Science B.V.)

We have previously shown that toxicity of the anticancer agent hydroxyurea (HU) in the rat is markedly increased by hypophysectomy or adrenalectomy. In this study, we investigated whether increased toxicity in ablated animals is a unique feature of HU or it is shared with other anticancer agents; the toxic effects of five such drugs have been compared in intact, hypophysectomized (HYX) and adrenalectomized (ADX) rats. Bis-chloroethyl-nitrosourea (BCNU, 5-10 mg/kg), busulfan (0.1-10 mg/kg), cyclophosphamide (25-125 mg/kg), 5-fluorouracil (15-75 mg/kg) and vindesine (0.1-0.5 mg/kg) were given to intact and endocrine-ablated rats, and lethality was recorded over 3 weeks. It was found that mortality was low or absent in intact rats, whereas (with the exception of HYX rats receiving the highest dose of busulfan) it was dramatically increased by both hypophysectomy and adrenalectomy. However, replacement treatments with long-acting tetracosactrin and corticosterone to HYX and ADX rats respectively afforded significant protection against BCNU toxicity only. We conclude that the integrity of the hypothalamo-pituitary-adrenal axis is needed to tolerate the toxicity of various anticancer drugs, although complex mechanisms appear to underlie such protective effect.

Treatment of mice with various doses (0, 0.25, 0.5, 1.0 and 2.0 mg/kg b.wt.) of vindesine resulted in a dose-dependent increase in the frequency of micronucleated polychromatic erythrocytes (MPCE) and micronucleated normochromatic erythrocytes. Conversely, the polychromatic erythrocyte and normochromatic erythrocyte (P/N ratio) ratio declined with increasing dose of vindesine. The dose effect relationship for MPCE, MNCE and P/N ratio was linear quadratic.