Antitumor activity of the new vinca-alkaloid S 12363 alone or in combination with verapamil on a human multidrug resistant renal carcinoma xenograft.
We have established a model of human renal cell carcinoma, Kgg2, transplanted into athymic nude mice which expressed P-glycoprotein (P-gp) (detected by flow cytometry) and a high level of mRNA transcript of mdr1 gene (Northern blot analysis). We have evaluated the antitumor activity of a new highly potent vinca-alkaloid derivative, S 12363, in comparison with the activity of the reference compound vinblastine (VLB), when used alone or in combination with verapamil (VRP). The influence of the calcium influx blocker verapamil on the activity of the combination of S 12363 with adriamycin (ADR) was also determined. The results showed that S 12363 at a dose of 0.05 mg/kg/day, administered alone by intraperitoneal route daily on days 1 to 5, induced a tumoral regression of 50% during the first days after treatment. This effect was potentialized by simultaneous treatment with verapamil at 20 mg/kg/day for 5 days, leading to a long-term reduction of 70% of tumor growth. Vinblastine at a dose of 0.4 mg/kg/day administered alone or in combination with verapamil, using the same protocol, was less efficient. The association of S 12363 at 0.075 mg/kg/day (on days: 1-5, 11, 21 and 31), adriamycin at 2 mg/kg/day (on days: 11, 21 and 31) and verapamil at 20 mg/kg/day (on days: 0-5, 11, 21 and 31) induced an important reduction of tumor growth of 80% at the end of the experiment. In conclusion, the new vinca-alkaloid derivative S 12363 could present a therapeutic advantage over the reference compound vinblastine in the treatment of renal cell carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)
Berlion
M
M
Institut de Recherches Internationale Servier, Division Thérapeutique Cancérologie, Courbevoie, France.
Arvelo
F
F
Leonce
S
S
Bourgeois
Y
Y
Rigaudy
P
P
Bizzari
J P
JP
Poupon
M F
MF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D004317:Doxorubicin / Q000008:administration & dosage; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology*; D014747:Vinblastine / Q000627:therapeutic use; D014748:Vinca Alkaloids / Q000008:administration & dosage / Q000627:therapeutic use*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D014748:Vinca Alkaloids; C064005:S 12363; D014747:Vinblastine; D004317:Doxorubicin; D014700:Verapamil