Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors

Abstract

The topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts comprising four lines of adult colon adenocarcinoma, three colon tumors derived from adolescents, six childhood rhabdomyosarcomas from previously untreated patients as well as sublines selected in vivo for resistance to vincristine and melphalan, and three lines of childhood osteogenic sarcoma. Efficacy was determined at maximal tolerated dose levels using intermittent i.p. administration [every 4 days for 4 doses (q4dx4)] or daily p.o. or i.p. administration 5 days per week for up to 20 courses. On a q4dx4 schedule, the maximum tolerated dose (MTD) was 12.5 mg/kg per administration, which caused marked weight loss and lethality in approximately 5% of the tumor-bearing mice. This schedule caused significant growth inhibition (but no tumor regression) in advanced adult colon adenocarcinomas. The minimal treated/control (T/C) ratios were 0.49, 0.54, and 0.3 for three of the tumor lines and were achieved at 18-21 days after the initiation of treatment. In contrast, rhabdomyosarcomas were considerably more sensitive, with T/C ratios being < 0.1 for three lines, whereas topotecan was less active against two other rhabdomyosarcoma xenografts (minimal T/C ratios, 0.17 and 0.14). As inhibitors of topoisomerase I have been demonstrated to have activity in the replication phase of the cell cycle (S-phase-specific), prolonged administration schedules were examined. Mice received topotecan 5 days per week for 3 weeks either by i.p. injection or by oral gavage (p.o.). In selected experiments, p.o. administration was continued for up to 20 weeks. Oral administration for 3 weeks (2 mg/kg per dose) resulted in complete regression of all six lines of rhabdomyosarcoma, with two lines demonstrating no regrowth during the period of observation (> or = 84 days). Similar results were obtained after i.p. administration, suggesting significant schedule dependency for these tumors. For colon tumors, the daily administration schedule (i.p. or p.o.) demonstrated some advantage over the intermittent schedule, resulting in partial regressions and significant inhibition of the growth of several colon adenocarcinoma lines. In rhabdomyosarcoma Rh12 and VRC5 colon adenocarcinoma, both of which demonstrated intermediate sensitivity to topotecan, and in osteosarcoma OS33, protracted p.o. administration for 13-20 weeks (1.0-1.5 mg/kg per dose given daily x 5 days) caused complete regression without regrowth in Rh12 and OS33 tumors and partial regression of all VRC5 tumors. No toxicity was observed using this schedule of administration. Topotecan demonstrated significant activity against all three osteosarcoma xenografts examined, with optimal schedules causing complete regression in two lines.(ABSTRACT TRUNCATED AT 400 WORDS)

Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase I inhibitor

“…Antitumour activity has been demonstrated in preclinical models and in phase I and II studies Rowinsky et al, 1992;Wall et al, 1992;Blaney et al, 1993;Hochster et al, 1994;Verweij et al, 1993;Creemers et al, 1994 for review). The results of preclinical and clinical studies indicate enhanced antineoplastic activity of topotecan when administered daily for prolonged periods of time (Giovanella et al, 1989;Burris et al, 1992;Houghton et al, 1992;Rowinsky et al, 1992;Hochster et al, 1994;Verweij et al, 1993). Also, preclinical studies with oral topotecan have shown that it has efficacy against rhabdomyosarcoma and colon carcinoma in mice (Houghton et al, 1992).…”

“…The results of preclinical and clinical studies indicate enhanced antineoplastic activity of topotecan when administered daily for prolonged periods of time (Giovanella et al, 1989;Burris et al, 1992;Houghton et al, 1992;Rowinsky et al, 1992;Hochster et al, 1994;Verweij et al, 1993). Also, preclinical studies with oral topotecan have shown that it has efficacy against rhabdomyosarcoma and colon carcinoma in mice (Houghton et al, 1992). The unique mechanism of action and lack of cross-resistance evidence with many wellknown currently available anti-tumour agents may provide therapeutic advantage in first-line or second-line chemotherapy.…”

Cytotoxic activity of topotecan in human tumour cell lines and primary cultures of human tumour cells from patients

“…A single optimal schedule could not be determined from the early preclinical in vivo studies (Dancey and Eisenhauer, 1996), although support for protracted schedules was obtained from some tumour model systems (Houghton et al, 1992). Nevertheless, the most commonly used clinical phase II schedule, a daily x five schedule, has been compared with more protracted schedules without any apparent advantage of the latter (Dancey and Eisenhauer, 1996).…”

The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan

“…Maximizing drug exposure to cells (particularly those with long cell-cycle times and low growth fractions) in S-phase can be achieved using protracted administration schedules such as daily for five days for two to three weeks (68). Studies of topotecan in xenograft models demonstrated the superiority of protracted schedules of administration over high doses administered Intermittently (68).…”

“…Maximizing drug exposure to cells (particularly those with long cell-cycle times and low growth fractions) in S-phase can be achieved using protracted administration schedules such as daily for five days for two to three weeks (68). Studies of topotecan in xenograft models demonstrated the superiority of protracted schedules of administration over high doses administered Intermittently (68). Based on the strength of these preclinical data, Santana and colleagues evaluated the protracted administration with pharmacokinetically guided dosing of topotecan to minimize variability in systemic exposure and achieve the putatively effective topotecan systemic exposure in children.…”