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Establishment of a Melphalan-resistant Rhabdomyosarcoma Xenograft with Cross-Resistance to Vincristine and Enhanced Sensitivity following Buthionine Sulfoximine-mediated Glutathione Depletion¹

Departments of Pediatrics [M. C. R, E. L., H. S. F.], Pathology [S. H. B., D. D. B., H. S. F.], and Medicine [G. B. E.], Duke University Medical Center, Durham, North Carolina 27710; The Johns Hopkins Oncology Center, Baltimore, Maryland 21205 [O. M. C.]; Department of Biochemistry, Cornell University Medical College, New York, New York 10021 [O. W. G.]; and Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38101 [J. K. H.]

A melphalan-resistant human rhabdomyosarcoma xenograft, TE-671 MR, was established in athymic mice by serial melphalan treatment of the parent xenograft, TE-671, at the 10% lethal dosage (LD₁₀); significant resistance was evident after ten passages of the tumor. TE-671 MR demonstrated a doubling time of 3.5 days and a latency period to 1000-mm³ tumors of 27.5 days. The glutathione level of TE-671 MR was 2.36 µmol/g tumor, wet weight, 2-fold higher than the parent line. The glutathione S-transferase activity of TE-671 MR was 117.8 µmol/min/mg protein, essentially unchanged from the parent line. Although TE-671 MR demonstrated cross-resistance to vincristine, dot blot analysis did not reveal an elevated expression of mdr1 mRNA in the resistant line. TE-671 MR demonstrated a 9.7-day growth delay following treatment with melphalan at the LD₁₀ (compared to 20.9 days for the parent line). Treatment with L-buthionine-SR-sulfoximine (BSO) resulted in increased sensitivity to melphalan subsequently administered at 50% of the LD₁₀ (melphalan alone, growth delays of 3.7 and 4.6 days in duplicate trials; melphalan plus BSO, growth delays of 7.2 and 9.8 days). Sensitivity to melphalan equal to that of the parent line TE-671 was not achieved, however. Treatment with BSO did not result in significantly enhanced sensitivity to subsequently administered vincristine (50% of the LD₁₀) (vincristine alone, growth delays of 6.8 and 6.9 days in duplicate trials; vincristine plus BSO, growth delays of 10.9 and 7.5 days). These results suggest that generation of melphalan resistance may be associated with development of cross-resistance to vincristine; this resistance may be associated with (although not necessarily mediated by) glutathione elevation; this resistance may be partially overcome by BSO-mediated depletion of glutathione.

¹ Supported by NIH Grants CA11898, CA43722, CA44460, CA23099, DK26912, NS20023, and NS00958; ACS Grant CH403; and Bristol-Myers 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 12/ 1/88. Revised 8/ 1/89. Accepted 9/12/89.