The therapeutic efficacy of gemcitabine, a new nucleoside analogue, was assessed in a variety of well-established human soft tissue sarcoma and ovarian cancer xenografts grown s.c. in nude mice. Tumour lines selected had different histological subtypes, growth rates and sensitivities to conventional cytostatic agents. The three different doses and schedules designed on the basis of a mean weight loss between 5% and 15% were i.p. injections of daily 3.5 mg kg-1 x 4, every 3 days 120 mg kg-1 x 4, and weekly 240 mg kg-1 x 2, which ultimately resulted in 19%, 10% and 4% toxic deaths, respectively. The weekly schedule induced > or = 50% growth inhibition in 2/4 soft tissue sarcoma and 4/6 ovarian cancer lines, while in three ovarian cancer lines > or = 75% growth inhibition was obtained. The anti-tumour effects of gemcitabine appeared to be similar or even better than previous data with conventional drugs tested in the same tumour lines. In comparison with the every 3 days schedule, the weekly and the daily schedule were less effective in 5/7 and 3/3 tumour lines (P < 0.001), respectively. In another experiment in three human tumour lines selected for their differential sensitivity to gemcitabine, weekly injections of 240 mg kg-1 x 6 did not result in a significant increase in the percentages of growth inhibition when compared to lower doses of 120 mg kg-1 or 60 mg kg-1 in the same schedule. However, the 240 mg kg-1 weekly x 6 schedule showed superior effects in 2/3 tumour lines in comparison with the same dose given every 2 weeks x 3 (P < 0.05). The preclinical activity of gemcitabine suggests that the drug can induce responses in soft tissue sarcoma and ovarian cancer patients. Our results further indicate that clinical trials of gemcitabine in solid tumour types should be designed on the basis of a schedule rather than a dose dependence.

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In preclinical studies, BNP7787 (disodium 2,2 0 -dithio-bis-ethane sulphonate), the disulphide form of mesna, has demonstrated selective protection against cisplatin-induced nephrotoxicity due to conversion into mesna inactivating toxic platinum species. Mesna (sodium 2-mercapto ethane sulphonate), however, can affect the antitumour activity of cisplatin, while BNP7787 does not interfere with the antitumour activity. To understand the difference in interference with cisplatin-induced antitumour activity between BNP7787 and mesna as well to characterise the selective nephroprotection by BNP7787, the pharmacokinetics of BNP7787 and mesna, each given i.v. 1000 mg kg À1 , were determined in plasma, kidney, liver, red blood cells (RBC), skeletal muscle and tumour of Fischer rats bearing subcutaneously implanted WARD colon tumours. The following results were obtained: (1) high concentrations of BNP7787 and mesna were observed in the plasma and kidney after administration of BNP7787 or mesna, except for mesna in plasma after BNP7787 administration; (2) in all other sampled compartments, the AUC values of both compounds were at least 5.5-fold lower than the corresponding values in kidney; (3) the AUC of mesna in plasma after mesna administration was comparable to the AUC of mesna in kidney after a dose of BNP7787 that can completely prevent cisplatin-induced nephrotoxicity in rats; (4) the AUC of mesna in plasma was five-fold higher relative to the AUC of mesna following BNP7787 administration (Po0.01). In conclusion, the five-fold higher AUC of mesna in plasma after mesna administration and the fact that mesna is more reactive with (hydrated) cisplatin than its disulphide form BNP7787 represent a plausible explanation as to why mesna administration can reduce the antitumour activity of cisplatin. After BNP7787 administration, the distribution of BNP7787 and mesna was restricted to the kidney, which confirmed the selective protection of the kidney by BNP7787.

CPT‐11, a semi‐synthetic derivative of camptothecin, was investigated for its activity in panels of 15 human ovarian‐cancer lines and 10 human soft‐tissue sarcoma lines grown s.c. in nude mice. Various factors were analyzed that may be of influence on the extent of tumor‐growth inhibition induced by CPT‐11. At equitoxic doses, CPT‐11 was more effective in the daily ×5 schedule than the weekly ×2 schedule, although a 2‐fold higher dose was administered in the weekly ×2 schedule. Since i.p. and i.v. injections were similarly effective, the selected treatment schedule was 20 mg/kg i.p. daily ×5, starting when tumors measured approximately 150 mm3. Growth inhibition of ≥75% was obtained in 8/15 human ovarian‐cancer lines and in 6/10 human soft‐tissue sarcoma lines. A weak correlation was found between topoisomerase‐I mRNA in xenograft tissues and sensitivity to CPT‐11. Relative topoisomerase‐I expression was highest in MRI‐H‐207 and WLS‐160 xenografts, in which CPT‐11 was able to induce cures of all tumors. The high efficacy in the 2 panels of human tumor lines suggests over‐prediction of its potential clinical activity in these tumor types. The difference in efficacy of CPT‐11 between species may be related to the metabolism of the drug, since CPT‐11 is converted more efficiently into SN‐38 in mice. In addition, mice may be less sensitive to SN‐38‐induced side‐effects. On the basis of the preclinical data, frequent administration of lower doses of CPT‐11 should be considered in order to increase response rates in the clinic. Int. J. Cancer 73:891–896, 1997. © 1997 Wiley‐Liss, Inc.