Therapeutic analysis of melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR.
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.
Lilley
E R
ER
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710.
Elion
G B
GB
Dewhirst
M W
MW
Schold
S C
SC
Blum
M R
MR
Savina
P M
PM
Laskowitz
D T
DT
Bigner
D D
DD
Friedman
H S
HS
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
D000970:Antineoplastic Agents; D005047:Etoposide; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D008558:Melphalan; D010100:Oxygen