Synergistic anti-tumor activity of a novel immunomodulator, BCH-1393, in combination with cyclophosphamide.
N,N-dimethylaminopurine pentoxycarbonyl D-arginine (BCH-1393) is a novel low molecular weight synthetic immunomodulator that has been shown to significantly stimulate cytotoxic T-lymphocyte responses both in vitro and in vivo (Zacharie B, Gagnon L, Attardo G, Connolly TP, St-Denis Y, Penney CL. Synthesis and activity of 6-substituted purine linker amine immunostimulants. J. Med. Chem. 1997;40:2883-94). Prompted by this evidence, we extended evaluation of BCH-1393 for anticancer activity in syngeneic mouse experimental tumor models. Consistent with previous findings, in vitro assessment of BCH-1393 activity demonstrated a significant increase in the CTL responses in the range of 10(-9)-10(-5) M. Treatment of mice with four consecutive daily intraperitoneal injections at 25 and 50 mg/kg resulted in a significant increase of the relative percentage of blood CD4+, CD8+, NK and monocyte subsets without any evidence of toxicity. In vivo anti-tumor activity of BCH-1393 was evaluated, either alone or in combination with subtherapeutic doses of cyclophosphamide (Cy), against weakly immunogenic mouse breast carcinoma DA-3 and strongly immunogenic colon adenocarcinoma MC38. Daily intraperitoneal injection of BCH-1393 at 50 mg/kg alone was well tolerated but produced a relatively weak anti-tumor effect in both tumor models. However, a significant inhibition of tumor outgrowth and suppression of established tumor growth was observed when BCH-1393 was administered in combination with subtherapeutic doses of Cy. Combination treatment of 50 mg/kg BCH-1393 with 100 mg/kg Cy (given as single intravenous bolus injection) starting 2 days prior to DA-3 tumor cell inoculation prevented tumor outgrowth in 70-80% of treated mice. In the remaining 20-30% of mice that had developed tumors, a nearly complete (90%) tumor growth inhibition was observed at days 22-24 post tumor implant. In the MC38 tumor model, combination treatment of established tumors with BCH-1393 and Cy (CTX) at 50 mg/kg resulted in a significant delay in tumor growth compared to CTX treatment alone. The observed concomitant anti-tumor activity of BCH-1393 with cyclophosphamide warrants further investigation of this immunomodulator as an adjunctive treatment of cancer.
Kadhim
S
S
BiochemPharma Inc., Que., Laval, Canada.
Penney
C
C
Lagraoui
M
M
Heibein
J
J
Attardo
G
G
Zacharie
B
B
Connolly
T
T
Gagnon
L
L
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use*; D003601:Cytotoxicity Tests, Immunologic; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; C108181:BCH 1393; D007166:Immunosuppressive Agents; D011687:Purines; D003520:Cyclophosphamide; D001120:Arginine