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Therapeutic Analysis of Melphalan-resistant Human Rhabdomyosarcoma Xenograft TE-671 MR¹

Departments of Pediatrics [E. R. L., D. T. L., H. S. F.], Medicine [G. B. E., S. C. S.], Radiology [M. W. D.], and Pathology [S. C. S., D. D. B., H. S. F.], and the Preuss Laboratory for Brain Tumor Research [D. D. B.], Duke University Medical Center, Durham, North Carolina 27710; and Burroughs Wellcome Company Research Triangle Park, North Carolina 27709 [M. R. B., P. M. S.]

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.

¹ This work was supported by NIH Grants CA11898, CA44640, NS00958, CA40355, NS20023; ACS Research Grant CH-403; and Bristol-Myers Research Grant 100-R18.

² To whom requests for reprints should be addressed, at P. O. Box 2916, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710.

Received 2/19/91. Accepted 5/23/91.