title: Modulation of cytostatic drugs by nifedipine in two heterotransplanted human testicular-cancer cell lines differing in their sensitivity to standard agents.
abstract: Drug resistance is an important clinical problem in testicular cancer patients with relapsed or refractory disease after first-line chemotherapy. Here we report that the relative reduction in tumour volume in nude mice heterotransplanted with either H 12.1 or H 23.1 human testicular cancer cell lines was significantly increased by addition of the calcium antagonist nifedipine to the maximum tolerated dose (MTD) of cisplatin (DDP). The mean reduction in relative tumour volume at day 30 (rVR) reached statistical significance for both cell lines following combination therapy of DDP with nifedipine compared to DDP alone (55 +/- 7% versus 12 +/- 4% for H 23.1 and 60 +/- 9% vs. DDP with nifedipine has also been confirmed in H 12.1 cells in vitro. However, in vivo, this combination was associated with a concordant increase in therapeutic toxicity. In contrast, no improvement in in vivo anti-tumour activity was obtained by combining similar dose-schedules of nifedipine with the MTD of epirubicin, or with MTDs of vinblastine or etoposide. These results are in agreement with our immunohistochemical finding that H 12.1 and H 23.1 do not over-express the Pgp 170 glycoprotein which mediates the multiple drug resistance (MDR) phenotype and involves both anthracyclines and vinblastine, but not DDP. We conclude that another Pgp-MDR modulator, nifedipine, is able to increase the anti-tumour activity of DDP in vivo and in vitro via a specific but as yet unknown mechanism, which is most likely not MDR-related. However, the increased anti-tumour activity is, in vivo, associated with a considerable increase in overall toxicity. Further studies are necessary to decrease therapeutic toxicity, before clinically relevant models for modifiers of DDP-resistance could possibly be applied to patients.
authors.affiliation: Department of Hematology/Oncology, Hanover University Medical School, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: T
authors.initials: T
authors.lastname: Dunn
authors.forename: A
authors.initials: A
authors.lastname: Harstrick
authors.forename: T
authors.initials: T
authors.lastname: Lerch
authors.forename: H
authors.initials: H
authors.lastname: Poliwoda
authors.forename: H J
authors.initials: HJ
authors.lastname: Schmoll
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D002352:Carrier Proteins / Q000032:analysis / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D004317:Doxorubicin / Q000627:therapeutic use / Q000633:toxicity; D004347:Drug Interactions; D004351:Drug Resistance; D015251:Epirubicin / Q000627:therapeutic use / Q000633:toxicity; D005047:Etoposide / Q000627:therapeutic use / Q000633:toxicity; D018237:Germinoma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009543:Nifedipine / Q000627:therapeutic use* / Q000633:toxicity; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014183:Transplantation, Heterologous; D014747:Vinblastine / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D015251:Epirubicin; D014747:Vinblastine; D005047:Etoposide; D004317:Doxorubicin; D009543:Nifedipine; D002945:Cisplatin