The schedule-dependent effects of the novel antifolate pralatrexate and gemcitabine are superior to methotrexate and cytarabine in models of human non-Hodgkin's lymphoma.
OBJECTIVE
Methotrexate is known to synergize with cytarabine [1-beta-D-arabinofuranosylcytosine (ara-C)] in a schedule-dependent manner. The purpose of this article is to compare and contrast the activity of pralatrexate (10-propargyl-10-deazaminopterin)/gemcitabine to the standard combination of methotrexate/ara-C and to determine if schedule dependency of this combination is important in lymphoma.


METHODS
Cytotoxicity assays using the standard trypan blue exclusion assay were used to explore the in vitro activity of pralatrexate and gemcitabine against a panel of lymphoma cell lines. Both severe combined imunodeficient beige and irradiated nonobese diabetic/severe combined imunodeficient mouse xenograft models were used to compare and contrast the in vivo activity of these combinations as a function of schedule. In addition, apoptosis assays were conducted.


RESULTS
Compared with methotrexate-containing combinations, pralatrexate plus gemcitabine combinations displayed improved therapeutic activity with some schedule dependency. The combination of pralatrexate and gemcitabine was superior to any methotrexate and ara-C combination in inducing apoptosis and in activating caspase-3. In vivo, the best therapeutic effects were obtained with the sequence of pralatrexate --> gemcitabine. Complete remissions were only appreciated in animals receiving pralatrexate followed by gemcitabine.


CONCLUSIONS
These data show that the combination of pralatrexate followed by gemcitabine was superior to methotrexate/ara-C in vitro and in vivo, and was far more potent in inducing apoptosis in a large B-cell lymphoma. These data provide strong rationale for further study of this combination in lymphomas where methotrexate and ara-C are used.
Toner
Lorraine E
LE
Laboratory of Experimental Therapeutics for the Lymphoproliferative Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
Vrhovac
Radovan
R
Smith
Emily A
EA
Gardner
Jeffrey
J
Heaney
Mark
M
Gonen
Mithat
M
Teruya-Feldstein
Julie
J
Sirotnak
Frank
F
O'Connor
Owen A
OA
D000630:Aminopterin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage* / Q000494:pharmacology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008727:Methotrexate / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
C418863:10-propargyl-10-deazaaminopterin; D003561:Cytarabine; D003841:Deoxycytidine; D000630:Aminopterin; D008727:Methotrexate; D000093542:Gemcitabine