SMANCS-Lipiodol emulsion is selectively deposited within tumor and the SMANCS is gradually released from the trapped Lipiodol into tumor tissues. SMANCS, which was developed in Japan, is one of a few practically available tumor-targeting agents.

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The problems of cytotoxic agents have been attributed to their low therapeutic indices and limited efficacy due to the non selective nature of their molecular targets and their inability to accumulate selectively in cancer tissues. Therefore, there is an urgent need to develop ways by which cytotoxic drugs can be selectively targeted to tumor tissue to allow them to act effectively against the cancer cells in the scene. The role of a drug delivery system(DDS) has drawn attention in this connection, Passive targeting is based on the so-called enhanced permeability and retention (EPR) effect. To use the EPR effect to full advantage, several techniques have been developed, namely, modification of the structures of drugs and development of drug carriers. In this review article, the results of preclinical and clinical studies of micelle-forming polymeric drug were described.

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MCC-465 is an immunoliposome-encapsulated doxorubicin (DXR). The liposorne is tagged with polyethylene glycol (PEG) and the F (ab') 2 fragment of a human monoclonal antibody named GAH which positively reacts to more than 90% of cancerous stomach tissues, though negative to all normal tissues. In pre-clinical studies, MCC-465 showed superior cytotoxic activity against several human stomach cancer cells compared to DXR or DXR-incorporated PEG-liposomes. Phase I trials ware carried out to define the maximum tolerated dose, dose limiting toxicity, recommended phase II dose and the pharmacokinetics of MCC-465. Patients(pts) with metastatic or recurrent stomach cancer were eligible for entry to phase I trial. MCC-465 was administered as an 1 hr infusion every 3 weeks and the treatment continued for up to 6 cycles. Twenty-three pts received a total of 62 courses at the 6.5 to 45.5 mg/m² dose level. DLTs were myelosuppression and appetite loss at the 45.5 mg/m² dose level. Other toxicities were mild. Neither palmar-plantar erythrodysesthesia (PPE) nor cardiotoxicity was observed. Acute reactions related to infusion were observed commonly in 16 pts in all the dose ranges. While no antitumor response was observed, NC was observed in 10 out of 18 evaluable pts. The pharmacokinetic study showed a similar AUC and Cmax to Doxil. MCC-465 was well tolerated. The recommended dose for phase I of MCC-465 for a three-week schedule was considered to be 32.5 mg/m².

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A hormonal therapy has been the first choice for advanced prostate cancer. Recently, LH-RH analogue whose clinical efficacy was considered equivalent to a castration and estrogens took a place of them and occupies a prominent position in a prostate cancer therapy. An LH-RH analogue and its controlled-release formulation led to a number of clinical trials not only as a monotherapy but also as an adjuvant of surgery and radiation therapy in various clinical situations. The development of controlled-release formulation of LH-RH analogue and a profile of its clinical trials were reviewed.

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The revised Pharmaceutical Affair Law was implemented in July 30, 2003. This law has made it possible for physicians to perform clinical trials of unapproved drugs or approved drugs for new indications and to use these trials for the New Drug Application. This system is referred to as “investigator-initiated registration-directed clinical trials”. “Investigator-initiated registration-directed clinical trials” must comply with the revised GCP. Therefore, physicians face great difficulty in performing such clinical trials, because physician are not familiar with the Pharmaceutical Affair Law and related regulations and majority of the medical institutions are not adequately equipped for the performance of such clinical trials. Potential problems and perspectives related to the investigator-initiated registration-directed clinical trials will be discussed.

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