title: Effects of KR-30035, a novel multidrug-resistance modulator, on the cardiovascular system of rats in vivo and on the cell cycle of human cancer cells in vitro.
abstract: The present study was performed to evaluate the adverse effects of KR-30035, a multidrug-resistance modulator, on the cardiovascular system in vivo, along with its effect on paclitaxel-induced cell cycle arrest in cultured cancer cells. In anesthetized rats, KR-30035 was about 10-fold less potent than verapamil in lowering blood pressure (i.v. ED20: 0.320+/-0.052 and 0.034+/-0.005 mg/kg, respectively) and in producing electrocardiogram changes. In conscious spontaneously hypertensive rats, verapamil caused a significant antihypertensive effects at the doses tested (p.o. ED20, 7.8+/-4.0 mg/kg), whereas KR-30035 did not significantly change either the blood pressure or the heart rate at any doses tested (up to 100 mg/kg). The estimated i.v. LD50 values in mice were 5.9 and 48.9 mg/kg for verapamil and KR-30035, respectively. In the presence of 10 microM KR-30035, paclitaxel (1 microM) when added to cultures of HCT15/CL02 human cancer cells greatly shifted the cell population from the G0/G1 phases towards G2/M phases (from 42.4, 30.3 and 27.3 to 14.6, 21.5 and 63.9% for the G0/G1, S and G2/M phases, respectively), with a similar magnitude to that of 10 microM verapamil (14.0, 15.7 and 70.3%, respectively). These results suggest that KR-30035 has weaker in vivo effects on the cardiovascular system compared with verapamil, while potentiating the G2/M arresting effect of paclitaxel on the cell cycle.
authors.affiliation: Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Yusong, Taejon.
authors.forename: B H
authors.initials: BH
authors.lastname: Lee
authors.forename: H S
authors.initials: HS
authors.lastname: Shin
authors.forename: C O
authors.initials: CO
authors.lastname: Lee
authors.forename: S H
authors.initials: SH
authors.lastname: Park
authors.forename: S E
authors.initials: SE
authors.lastname: Yoo
authors.forename: K Y
authors.initials: KY
authors.lastname: Yi
authors.forename: N P
authors.initials: NP
authors.lastname: Jung
authors.forename: S U
authors.initials: SU
authors.lastname: Choi
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects*; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051379:Mice; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; C111621:KR 30035; D013764:Tetrahydronaphthalenes; D014700:Verapamil