シスプラチンとペプロマイシンの併用療法における相乗効果発現の機序に関する研究

抄録

Cisplatin (CDDP) and peplomycin (PEP) are effective new agents for chemotherapy of head and neck cancer. And the combination therapy of the two drugs is considered to have good synergistic effects. Despite the observances made in both basic experiments as well as in clinical trials, the mechanism of synergism, however, remains unknown. Experimental studies, therefore, were made to solve the mechanism of synergism.
First, combination therapy with CDDP and PEP was performed, using Ehrlich ascites carcinoma, in actual clinical dose schedule. CDDP was administered intra-peritoneally at day 0, and PEP 48 hours later (day 3). This combination therapy with CDDP and PEP proved to have good synergistic effects.
As for the mechanism of synergism, one of the hypotheses was as follows. It was thought that nonprotein-bound CDDP with anti-cancer activity might be released from protein-bound CDDP when PEP is administered in combination. But after the experiment in vitro, using dog plasma, my conclusion is that CDDP is bound to plasma protein irreversivelythus denying this hypothesis.
The next study for the mechanism was to see the effects against cell cycle progression by flowcytometry process. It was found that at an early stage after single administration of CDDP, cell cycle progression was delayed in S phase and blocked in G2 phase thereafter. Forty-eight hours after administration of CDDP, cells accumulated in G2-M phase. This change, however, proved to be reversible because cells returned to normal progression pattern 96 hours after single administration of CDDP. As for PEP in single administration, cell cycle progression was blocked in G2-M phase at an early stage; it was also reversible. In the case of combination therapy, cell cycle progression pattern proved irreversible, and damaged cells (debris) appeared at low channels. It is, therefore, assumed that cells are seriously and irreversibly damaged in combination therapy.
As result of the zoregoing studies, one of the mechanism of synergism is thought to be as follows:
After administration of CDDP, cells are accumulated in G2-M phase. PEP is administered 48 hours after CDDP treatment when cells are most accumulated in G2-M phase. This brings about PEP's most efficient cytocydal effects since PEP has high sensitivity against cells in G2-M phase. This may explain one of the mechanism of synergism. And the high clinical respose rate in combination therapy of CDDP and PEP - when the former is administered first and the latter 48 hours after CDDP treatment - may be due to this mechanism.