Protein-bound
polysaccharide-K (PSK) enhances the antitumor effect of anticancer
drug when used clinically in combination with such drugs. PSK is known to act by immune-mediated mechanisms; however, the relationship between PSK and metabolic
enzymes of anticancer drugs is unknown. We used the
collagen gel droplet-embedded culture
drug sensitivity test (CD-DST) clinically to evaluate the sensitivity of anticancer drugs. In the present study, we modified the CD-DST by adding peripheral blood mononuclear cells (PBMCs) (immuno-CD-DST) and examined the antitumor effect of PSK in combination with anticancer drugs. First, HCT116 human
colon cancer cells were cultured with PSK and
5-fluorouracil (5-FU) or
5'-deoxy-5-fluorouridine (5'-DFUR) in the presence or absence of PBMCs, and the antiproliferative effects were compared. In the presence of PBMCs, PSK augmented the inhibitory effects of
5-FU and
5'-DFUR on HCT116 cell proliferation. Next, using human
gastric cancer and
colon cancer cell lines, the effects of PSK on
mRNA expression of various metabolic
enzymes of fluoropyrimidines:
dihydropyrimidine dehydrogenase (DPD),
thymidylate synthase,
thymidine phosphorylase and orotate phosphoribosyl
transferase, were examined by real-time PCR. PSK significantly enhanced DPD
mRNA expression in all of the
cancer cell lines tested, but not those of the other
enzymes. Addition of IFN-α and TRAIL,
cytokines known to inhibit DPD expression, to the cultures reduced DPD
mRNA expression in the
cancer cells. When PBMC samples collected from healthy volunteers were cultured with PSK, IFN-α
mRNA expression increased in 3 of the 5 PBMC samples, while TRAIL
mRNA expression was unchanged. The present results propose the possibility that PSK induces PBMCs to express IFN-α which inhibits DPD expression, and consequently augments the antitumor effect of
5-FU or
5'-DFUR. Immuno-CD-DST is useful for evaluating drugs with immunological mechanisms of action.