title: Therapeutic analysis of melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR.
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.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: E R
authors.initials: ER
authors.lastname: Lilley
authors.forename: G B
authors.initials: GB
authors.lastname: Elion
authors.forename: M W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: S C
authors.initials: SC
authors.lastname: Schold
authors.forename: M R
authors.initials: MR
authors.lastname: Blum
authors.forename: P M
authors.initials: PM
authors.lastname: Savina
authors.forename: D T
authors.initials: DT
authors.lastname: Laskowitz
authors.forename: D D
authors.initials: DD
authors.lastname: Bigner
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000633:toxicity; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D008297:Male; D008558:Melphalan / Q000378:metabolism / Q000494:pharmacology*; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010100:Oxygen / Q000502:physiology; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D005047:Etoposide; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D008558:Melphalan; D010100:Oxygen