The dithiane Ro 44-5912 enhances vinblastine sensitivity of drug resistant and parental KB lines in vivo.
The multidrug resistance modifying activity of a dithiane analogue of tiapamil, Ro 44-5912, was examined in vivo. Results of acute toxicity studies in mice indicated that lethal toxicity occurred with doses greater than 1 mmol/kg of body weight. In a preliminary pharmacokinetic investigation, Ro 44-5912 appeared to have a longer half-life in mice than did its (R) enantiomer Ro 44-5911 (3.15 +/- 0.02 h versus 2.15 +/- 0.14 h) as measured by total radiolabel in plasma. In non-tumour bearing mice, Ro 44-5912 enhanced the toxicity of vinblastine in a manner that was dependent on the dose of both drugs. Vinblastine did not have a significant effect on tumour growth when given to nude mice bearing the parental cell line KB-3-1 at a dose of 1.5 mg/kg once per week for 3 weeks. Combination treatment with Ro 44-5912 markedly enhanced the antitumour activity of vinblastine. Similar results were seen when KB-3-1 tumours were treated with the combination of vinblastine plus cyclosporin A. Another tiapamil analogue, Ro 11-2933, had no enhancing activity with this tumour when used at an equitoxic combination dose. Ro 44-5912 also significantly enhanced vinblastine activity with P-glycoprotein-expressing KB-8-5 tumours. In three independent experiments, Ro 44-5912 enhanced the growth inhibiting activity of vinblastine by a mean of approximately 40%. Neither Ro-11-2933 nor cyclosporin A, at the maximal tolerated doses in combination with vinblastine, led to significant inhibition of KB-8-5 tumour growth compared to treatment with the two vehicles alone. These results show that Ro 44-5912 is an active modulator of drug resistance in vivo.
Eliason
J F
JF
Karmanos Cancer Institute, Detroit, Michigan 48201-1379, USA.
Sawada
R
R
Tsukaguchi
T
T
Kobayashi
K
K
Ichihara
S
S
Konishi
C
C
Horii
I
I
Kuruma
I
I
Ramuz
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D003524:Cyclosporins / Q000008:administration & dosage; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007624:KB Cells / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011437:Propylamines / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D014665:Vasodilator Agents / Q000494:pharmacology; D014747:Vinblastine / Q000009:adverse effects / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D003524:Cyclosporins; D011437:Propylamines; D014665:Vasodilator Agents; C089102:cyclosporin A, 4-(2-butenyl)-4,4,N-trimethylthreonine(1)-; D014747:Vinblastine; C054970:Ro 11-2933