Antitumor activity of enkephalin analogues in inhibiting PYB6 tumor growth in mice and immunological effects of methionine enkephalinamide.
Recent evidence has implicated enkephalins as immunomodulators. Several studies have reported the regulation of tumor growth by methionine enkephalin (ME). However, there has been little effort to relate the immunological significance of enkephalins to the development of anticancer drugs. The present study had three aims: first, to compare the antitumor activity of the synthetic peptide, D-[Ala2]methionine enkephalinamide (MEA), with endogenous enkephalins on PYB6 fibrosarcoma tumor growth; second, to determine whether tumor growth inhibition was mediated by an opiate receptor; and third, to investigate the effects of MEA on selected immune responses. Female B6C3F1 mice were injected i.p. daily for 7 days with 50-4000 micrograms/kg of ME, MEA, leucine enkephalin (LE) or D-[Ala2]leucine enkephalinamide (LEA), beginning 1 day after PYB6 inoculation. ME and MEA, but not LE or LEA, decreased the PYB6 growth rate. The dose of 50 micrograms/kg MEA exerted the maximum inhibition of tumor growth (nearly 72% on day 15 post tumor transplantation). MEA was not directly toxic to PYB6 tumor cells, as evaluated by the measurement of DNA synthesis and cellular ATP levels of PYB6 cells exposed to MEA in vitro. No [3H]-etorphine specific bindings were detected on the cell membrane or sonicates of splenic lymphocytes or PYB6 cells. Therefore, the antitumor activity by MEA is likely mediated by an indirect mechanism. Immunological studies indicated that MEA selectively enhanced the lymphoproliferative response to the T-cell mitogen, concanavalin A, but not to the B-cell mitogen, lipopolysaccharide.(ABSTRACT TRUNCATED AT 250 WORDS)
Srisuchart
B
B
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613.
Fuchs
B A
BA
Sikorski
E E
EE
Munson
A E
AE
Loveless
S E
SE
D000276:Adjuvants, Immunologic; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000970:Antineoplastic Agents; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004745:Enkephalins / Q000494:pharmacology; D005260:Female; D005354:Fibrosarcoma; D007694:Killer Cells, Natural / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D011957:Receptors, Opioid / Q000032:analysis; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D004745:Enkephalins; D011957:Receptors, Opioid; D009270:Naloxone; D004744:Enkephalin, Methionine; C021055:Met-enkephalinamide