A patient with adrenocortical carcinoma: characterization of its biological activity and drug resistance profile.
We describe a patient with a metastasized adrenocortical cancer who exhibited excessive production of both glucocorticoids and mineralocorticoids combined with suppressed androgen production. Unusual steroid metabolites found in the patient's urine have not been described previously in association with this tumor type. Investigation of the multidrug resistance phenotype in single-cell suspensions of the tumor revealed low expression of multidrug resistance protein but high expression of P-glycoprotein (Pgp) and lung resistance-related protein. Functional Pgp in these tumor cells was shown by the modulatory effect of PSC833 on daunorubicin accumulation. Mitotane, at a concentration achieved in this patient's plasma, completely reversed the Pgp-related resistance both in the Pgp-overexpressing KB8-5 cell line and in the patient's tumor cells. On the basis of these in vitro results, the patient was treated with a combination of multidrug resistance drugs (doxorubicin, vincristine, and etoposide) plus mitotane as a Pgp modulator. This treatment was ineffective, however. A chemosensitivity assay demonstrated that the tumor cells were highly resistant to the drugs used. The adrenocortical cancer cells expressed mutant p53, and no evidence for induction of apoptosis by these drugs was found.
Feller
N
N
Central Laboratory for Clinical Chemistry, Academic Hospital, Groningen, 9700 RB Groningen, The Netherlands.
Hoekman
K
K
Kuiper
C M
CM
Linn
S C
SC
Verheul
H M
HM
Wolthers
B G
BG
Popp-Snijders
C
C
Pinedo
H M
HM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000306:Adrenal Cortex Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D000328:Adult; D000728:Androgens / Q000652:urine; D000970:Antineoplastic Agents / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D002277:Carcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000633:toxicity; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000008:administration & dosage; D016158:Genes, p53; D005938:Glucocorticoids / Q000652:urine; D006801:Humans; D008297:Male; D008901:Mineralocorticoids / Q000652:urine; D008939:Mitotane / Q000008:administration & dosage; D009363:Neoplasm Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics; D014750:Vincristine / Q000008:administration & dosage; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000728:Androgens; D000970:Antineoplastic Agents; D003630:Daunorubicin; D004317:Doxorubicin; D005047:Etoposide; D005938:Glucocorticoids; D008901:Mineralocorticoids; D008939:Mitotane; D009363:Neoplasm Proteins; D020394:Vault Ribonucleoprotein Particles; D014750:Vincristine; D000099187:Major Vault Protein