A phase I clinical and pharmacokinetic study of the multi-drug resistance protein-1 (MRP-1) inhibitor sulindac, in combination with epirubicin in patients with advanced cancer.
OBJECTIVE
Multi-drug resistance mediated by ATP-binding cassette trans-membrane protein pumps is an important cause of cancer treatment failure. Sulindac has been shown to be a competitive substrate for the clinically important resistance protein, multi-drug resistance protein-1 (MRP-1), and thus might enhance the anti-cancer activity of substrate chemotherapeutic agents, e.g. anthracyclines.


METHODS
We conducted a dose-escalating, single arm, prospective, open label, non-randomised phase I trial of epirubicin (75 mg/m(2)) in combination with escalating oral doses of sulindac (0-800 mg) in patients with advanced cancer to identify an appropriate dose of sulindac to use in future resistance studies. Anthracycline and sulindac pharmacokinetics were studied in cycles 1 and 3.


RESULTS
Seventeen patients (8 breast, 3 lung, 2 bowel, 1 melanoma, 1 renal, 1 ovarian and 1 of unknown primary origin, 16/17 having had prior chemotherapy) were enrolled. Eight patients received a full six cycles of treatment; 14 patients received three or more cycles. Dose-limiting toxicity was observed in two patients at 800 mg sulindac (1 renal impairment, 1 fatal haemoptysis in a patient with advanced lung cancer), and sulindac 600 mg was deemed to be the maximum tolerated dose. Sulindac had no effect on epirubicin pharmacokinetics. Among 15 patients with evaluable tumour, two partial responses were seen (malignant melanoma and breast cancer). Four others had prolonged stable disease.


CONCLUSIONS
Epirubicin 75 mg/m(2) and sulindac 600 mg are the recommended doses for phase II studies for these agents in combination.
O'Connor
R
R
The National Institute for Cellular Biotechnology, Dublin City University, Dublin, 9, Ireland. robert.oconnor@dcu.ie
O'Leary
M
M
Ballot
J
J
Collins
C D
CD
Kinsella
P
P
Mager
D E
DE
Arnold
R D
RD
O'Driscoll
L
L
Larkin
A
A
Kennedy
S
S
Fennelly
D
D
Clynes
M
M
Crown
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015251:Epirubicin / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010976:Platelet Count; D011446:Prospective Studies; D013467:Sulindac / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014336:Troponin / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000903:Antibiotics, Antineoplastic; D014336:Troponin; D013467:Sulindac; D015251:Epirubicin; D003404:Creatinine