In vitro evaluation of flavopiridol, a novel cell cycle inhibitor, in bladder cancer

Abstract

Flavopiridol is a novel cell cycle inhibitor that may be a useful agent in bladder cancers with tumor suppressor gene alterations and/or multidrug resistance.

Small-molecule cyclin-dependent kinase modulators

“…Again, the apoptotic effect was independent of p53 status and was associated with the depletion of cyclin D1 (Patel et al, 1998). These findings have been corroborated in other preclinical models (Bible and Kaufmann, 1996;Schrump et al, 1998;Chien et al, 1999;Shapiro et al, 1999b). Efforts to understand flavopiridol-induced apoptosis are under intense investigation.…”

“…Furthermore, synergistic effects with cisplatin were not schedule dependent (Bible and Kaufmann, 1997). However, Chien et al (1999) failed to demonstrate a synergistic effect between flavopiridol and cisplatin and/or g-irradiation in bladder carcinoma models. One important issue to mention is that most of these studies were performed in in vitro models.…”

Small molecule modulators of cyclin-dependent kinases for cancer therapy

“…Similar p53-independent apoptosis was observed when¯avopiridol was tested against a panel of squamous head and neck cell lines, including a head and neck cell line (HN30), insensitive to several DNA damaging agents including g-XRT and bleomycin (Patel et al, 1998). Other groups corroborated these ®ndings in other preclinical models (Achenbach et al, 2000;Bible and Kaufmann, 1996;Chien et al, 1999;Guedez et al, 1999;Kitada et al, 2000;Li et al, 2000a,b;Park et al, 1996;Schrump et al, 1998). Preliminary evidence from our laboratory demonstrated that¯avopiridol-induced apoptosis in leukemia cell lines is associated with early activation of the MAPK protein kinase family (MEK, p38 and JNK) (Lahusen et al, 2000).…”

“…Moreover, the synergistic e ects seen with cisplatin were not schedule-dependent (Bible and Kaufmann, 1997). Furthermore, the synergism between¯avopiridol with cisplatin and/or g-irradiation did not occur in bladder carcinoma models; however,¯avopiridol demonstrated even more potent e ects on tumor cell lines that overexpress MDR (Chien et al, 1999). These extensive preclinical data will be of help to design clinical trials to test these combinations/schedules in the clinic.…”

Karenitecin (bnp1350) and flavopridol as radiosensitizers in malignant glioma

“…In summary, flavopiridol is a synthetic flavone, which has previously been evaluated as an antineoplastic agent [6][7][8][16][17][18][19][20][21] . It is a well-tolerated drug; the dose used in clinical trials ranges between 0.1-0.2 mg/ml.…”