Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening.
We have established ten transplantable human soft-tissue sarcoma (STS) xenografts grown as subcutaneous tumours in the nude mouse. Nine xenografts originated from patients that needed chemotherapy in the course of their disease. The xenografts were tested for their sensitivity to maximum tolerated doses of five anti-cancer agents. Growth of treated tumours was expressed as a percentage of control tumour growth and a growth inhibition > 75% was measured for doxorubicin in 20% of the STS xenografts, for cyclophosphamide in 30%, for ifosfamide in 20%, for vincristine in 20%, whereas etoposide was not effective in the STS xenografts. In three out of ten STS xenografts MDR1 mRNA was detectable, but this was not related to the resistance against doxorubicin, vincristine or etoposide. Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide. In all STS tissues, however, these levels were lower than topoisomerase IIalpha mRNA in a drug-sensitive human ovarian cancer xenograft. Glutathione concentrations and the activities of glutathione S-transferase, glutathione peroxidase and glutathione reductase were not related to resistance against the alkylating agents or doxorubicin. Of interest, in all STS tissues, glutathione S-transferase pi was the predominant isoenzyme present. In conclusion, chemosensitivity of the STS xenografts reflects clinical response rates in phase II trials on the same compounds in adult STS patients. Relatively low levels of topoisomerase IIalpha mRNA may partly account for intrinsic resistance against, for example, doxorubicin. Additional factors must contribute to moderate responsiveness to alkylating agents.
Boven
E
E
Department of Medical Oncology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Pinedo
H M
HM
van Hattum
A H
AH
Scheffer
P G
PG
Peters
W H
WH
Erkelens
C A
CA
Schlüper
H M
HM
Kuiper
C M
CM
van Ark-Otte
J
J
Giaccone
G
G
D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019450:Genes, MDR; D007527:Isoenzymes / Q000235:genetics; D016014:Linear Models; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000235:genetics; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000235:genetics; D014183:Transplantation, Heterologous
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D004250:DNA Topoisomerases, Type II