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Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts
W C Zamboni1, C F Stewart, J Thompson
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105-2974, USA.
Background:
Topotecan is a topoisomerase I inhibitor with activity against xenografts of childhood solid tumors and established clinical activity against neuroblastoma and rhabdomyosarcoma. We have studied the relationship between systemic exposure to and the antitumor activity of topotecan lactone (the active form of the drug) in the xenograft models. Furthermore, we determined whether the responses seen in these models occur at systemic exposure levels that are tolerable in children.
Methods:
Neuroblastoma xenografts derived from the tumors of six different patients were established subcutaneously in immune-deprived mice. Topotecan was administered by intravenous bolus injection 5 days a week for 2 consecutive weeks, repeated every 21 days for three cycles. The minimum daily doses that induced complete responses (CRs) and partial responses (PRs) were determined. Topotecan lactone pharmacokinetic studies were performed in both tumor-bearing and nontumor-bearing mice.
Results:
The minimum doses associated with CRs and PRs in four of the six neuroblastoma xenografts were 0.61 and 0.36 mg/kg body weight, respectively. The topotecan lactone single-day systemic exposures associated with these doses were 88 and 52 ng x hr/mL, respectively. There was an approximately sixfold difference in topotecan lactone systemic exposure (290 ng x hr/mL versus 52 ng x hr/mL) associated with achieving CRs in the least-sensitive and most-sensitive tumors, respectively.
Conclusions:
Neuroblastoma xenografts are highly sensitive to topotecan therapy, and responses in mice are achieved at systemic exposures similar to those that are clinically effective and tolerable in children. These results support the concept of deriving preclinical data relating systemic exposure to antitumor activity in xenograft models. Such data may be valuable in making informed decisions regarding the clinical development of new agents.
Insights
Topotecan effectively treats neuroblastoma xenografts at tolerable systemic exposure levels. This study links drug exposure to antitumor activity, supporting its clinical development in children.
Area of Science:
- Pharmacology
- Oncology
- Pediatric Cancer Research
Background:
- Topotecan, a topoisomerase I inhibitor, shows efficacy against childhood solid tumors, including neuroblastoma and rhabdomyosarcoma.
- This study investigates the correlation between systemic exposure to topotecan lactone and its antitumor activity in xenograft models.
- The research also assesses if observed responses occur at child-tolerable systemic exposure levels.
Purpose of the Study:
- To establish the relationship between systemic exposure of topotecan lactone and its antitumor effects in neuroblastoma xenograft models.
- To determine if the therapeutic exposures in xenograft models are clinically relevant and tolerable for pediatric patients.
Main Methods:
- Neuroblastoma xenografts from six patients were implanted in mice.
- Topotecan was administered intravenously over three cycles, with dose-ranging to determine minimum effective doses for complete (CR) and partial responses (PR).
- Pharmacokinetic studies of topotecan lactone were conducted in tumor-bearing and non-tumor-bearing mice.
Main Results:
- Minimum doses for CR and PR in four of six xenografts were 0.61 and 0.36 mg/kg, respectively.
- Associated systemic exposures for CR and PR were 88 and 52 ng x hr/mL, respectively.
- A sixfold variation in systemic exposure was observed between the most and least sensitive tumors for CR.
Conclusions:
- Neuroblastoma xenografts demonstrate high sensitivity to topotecan.
- Therapeutic responses in mice occur at systemic exposures comparable to those effective and tolerable in children.
- Preclinical data correlating systemic exposure with antitumor activity in xenograft models are valuable for guiding clinical development of new agents.