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Therapeutic analysis of melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR
E R Lilley1, G B Elion, M W Dewhirst
1Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710.
Abstract:
Investigations with the melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR were carried out to identify patterns of cross-resistance and collateral sensitivity and to define the mechanism(s) mediating melphalan resistance. TE-671 MR was cross-resistant to thio-TEPA, mitomycin, vincristine, and cisplatin, and partially resistant to chlorambucil and cyclophosphamide. TE-671 MR and the parent line TE-671 were both resistant to 1,3-bis(2-chloroethyl)-nitrosourea and expressed similar levels of O6-alkylguanine-DNA alkyltransferase. TE-671 MR retained full sensitivity to actinomycin D and demonstrated enhanced sensitivity to VP-16 compared to TE-671. Treatment of TE-671 MR with melphalan plus VP-16 resulted in greater than additive growth delays. The frequency of hypoxic regions was similar in TE-671 MR and TE-671, respectively. Measurement of tumor-to-plasma levels at 180 min following i.p. administration of melphalan at 0.5 of the 10% lethal dosage showed mean tumor-to-plasma ratios of 3.81 in TE-671 MR and 7.38 in TE-671, respectively. The lower drug levels in TE-671 MR may be contributing to the resistance to melphalan and thus indicate the need for further studies to define the reasons for these differences in tumor drug level.
Insights
Melphalan-resistant rhabdomyosarcoma xenografts show cross-resistance to several chemotherapy drugs. However, they exhibit enhanced sensitivity to VP-16, suggesting potential combination therapy strategies.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Melphalan resistance is a significant challenge in rhabdomyosarcoma treatment.
- Understanding cross-resistance and collateral sensitivity is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate cross-resistance and collateral sensitivity patterns in melphalan-resistant human rhabdomyosarcoma xenografts (TE-671 MR).
- To elucidate the mechanisms underlying melphalan resistance in this model.
Main Methods:
- In vitro and in vivo drug sensitivity testing of TE-671 MR xenografts.
- Assessment of O6-alkylguanine-DNA alkyltransferase levels.
- Evaluation of tumor drug levels following melphalan administration.
Main Results:
- TE-671 MR xenografts displayed cross-resistance to thio-TEPA, mitomycin, vincristine, and cisplatin, with partial resistance to chlorambucil and cyclophosphamide.
- Similar O6-alkylguanine-DNA alkyltransferase levels were observed in TE-671 MR and parent TE-671 cells.
- TE-671 MR showed retained sensitivity to actinomycin D and enhanced sensitivity to VP-16.
- Combination therapy with melphalan and VP-16 resulted in synergistic growth delays.
- Lower tumor-to-plasma melphalan levels were detected in TE-671 MR compared to TE-671.
Conclusions:
- Melphalan resistance in TE-671 MR is associated with cross-resistance to several agents but collateral sensitivity to VP-16.
- Reduced tumor drug levels may contribute to melphalan resistance.
- Further research is needed to define the exact mechanisms of melphalan resistance and optimize combination therapies.