Overcoming drug resistance in cancer cells with synthetic isoprenoids.
A cultured subline (P388/ADM) of mouse P388 leukemia resistant to doxorubicin, vinblastine, vincristine, dactinomycin, and daunorubicin became sensitive again when treated with noncytotoxic doses of either of two synthetic isoprenoids: N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine (SDB-ethylenediamine) and N-(p-methylbenzyl)decaprenylamine X HCI (PMB-decaprenylamine). The isoprenoids also reversed resistance to doxorubicin and vincristine in a cultured vincristine-resistant P388 leukemia subline (P388/VCR). Median lethal doses (LD50) for PMB-decaprenylamine and SDB-ethylenediamine administered ip were 123 and 350 mg/kg against mice, whereas the LD50 for verapamil, another modifier of cellular drug resistance, was about 7.6 mg/kg. In vivo experiments with P388/VCR-bearing mice showed that both SDB-ethylenediamine and verapamil overcame vincristine resistance, but PMB-decaprenylamine showed only slight activity. SDB-ethylenediamine was especially effective, overcoming the vincristine resistance at 1 mg drug/kg. Since the structure of SDB-ethylenediamine resembles that of verapamil, a calcium-blocking agent that overcomes drug resistance, it was checked for calcium-blocking activity. However, calcium channel-blocking activity was not observed with 20 micrograms isoprenoid/ml, whereas calcium channel activity was completely blocked by 1 microgram verapamil/ml.
Yamaguchi
T
T
Nakagawa
M
M
Shiraishi
N
N
Yoshida
T
T
Kiyosue
T
T
Arita
M
M
Akiyama
S
S
Kuwano
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D005029:Ethylenediamines / Q000494:pharmacology* / Q000633:toxicity; D007928:Lethal Dose 50; D007941:Leukemia P388 / Q000188:drug therapy* / Q000401:mortality; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D013729:Terpenes / Q000494:pharmacology* / Q000633:toxicity; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D005029:Ethylenediamines; C043082:N-(4-methylbenzyl)decaprenylamine; D013729:Terpenes; C048678:N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine; D014750:Vincristine; D004317:Doxorubicin; D014700:Verapamil; D002118:Calcium