Sequence dependence of Alimta (LY231514, MTA) combined with doxorubicin in ZR-75-1 human breast carcinoma cells.
Alimta is a new-generation antifolate with inhibitory activity against multiple enzymes, including thymidylate synthase, glycinamide ribonucleotide formyltransferase and dihydrofolate reductase. Alimta is undergoing broad phase II evaluation as a single agent, and preliminary results show responses in several tumor types, including breast carcinoma. Doxorubicin is often used in combination chemotherapy of breast cancer. Because the two drugs have mechanisms of action that might be complementary, we investigated a possible synergism between doxorubicin and Alimta on growth inhibition of ZR-75-1 human breast carcinoma cells. Cytostatic activity was evaluated using semi-automated MTT assays, and drug interactions were determined using CalcuSyn (Chou/Hayball) multiple drug effect analyses. The cells were exposed to Alimta or doxorubicin as single agents and combinations for 24 hours starting at the time of plating or for 72 hours starting 24 hours after plating with a total culture time of 96 hours. Preincubation with Alimta for 24 hours followed by exposure to doxorubicin for 72 hours resulted in highly synergistic activity, whereas the opposite sequence or simultaneous exposure produced mainly an additive response. DNA flow cytometry studies indicated that Alimta causes a build-up of cells near the G1/S interface after 24 hours of incubation. The data suggest that, to obtain maximal antitumor activity, Alimta should precede doxorubicin when the drugs are given in combination chemotherapy protocols.
Schultz
R M
RM
Cancer Research Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Dempsey
J A
JA
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005971:Glutamates / Q000008:administration & dosage; D006131:Growth Inhibitors / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000068437:Pemetrexed; D014407:Tumor Cells, Cultured
D005971:Glutamates; D006131:Growth Inhibitors; D000068437:Pemetrexed; D006147:Guanine; D004317:Doxorubicin