Screening of potential prodrugs on cells derived from Dupuytren's disease patients.
Dupuytren's disease (DD) is a fibroproliferative disorder, the cure for which is still limited to surgical excision of the affected fascia, often leading to high recurrence rates. Due to this fact, non-surgical treatments are being investigated, among them those targeting molecular processes of proliferation and differentiation in Dupuytren's cell cultures. Drugs with antiproliferative action may be valuable in DD treatment. Through characterization of changes on DD-specific cells, we, therefore, decided to test the therapeutic potential of new cytostatic drugs for DD treatment and/or for reduction of post-operative recurrence rates. The N-sulfonylpyrimidine derivative, amidino-substituted benzimidazo[1,2-a]quinoline, and amidino dihydrothienothienyl[2,3-c]quinolone hydrochloride, known to affect proliferation processes, were tested for their antiproliferative activity on primary fibroblasts/myofibroblasts cell cultures derived from the palmar fascia of patients with DD. Only amidino dihydrothienothienyl[2,3-c]quinolone hydrochloride acted in a highly specific manner on cells derived from diseased fascia of DD patients and exhibited a low cytotoxic effect. This result might be a consequence of its specific activity on cytoskeleton changes occurring in differentiating cells. A similar short-term differential antiproliferative effect was observed by the N-sulfonylpyrimidine derivative that was, however, completely lost after 6- and 14-day treatments. The amidino-substituted benzimidazo[1,2-a]quinoline exerted a strong non-specific, dose-related antiproliferative activity on cell types.
Kraljevic Pavelic
Sandra
S
Laboratory of Systems Biomedicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka Cesta 54, 10000 Zagreb, Croatia. skraljevic@irb.hr
Bratulic
Sinisa
S
Hock
Karlo
K
Jurisic
Davor
D
Hranjec
Marijana
M
Karminski-Zamola
Grace
G
Zinic
Biserka
B
Bujak
Maro
M
Pavelic
Kresimir
K
D016022:Case-Control Studies; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004387:Dupuytren Contracture / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D005205:Fascia / Q000187:drug effects* / Q000473:pathology; D000071938:Fasciotomy; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D012008:Recurrence; D013329:Structure-Activity Relationship; D013997:Time Factors
D011355:Prodrugs; D011743:Pyrimidines; D011804:Quinolines; D015363:Quinolones