A 59-year-old female underwent mastectomy for right breast cancer in November 1992. She received tamoxifen and anthracycline-containing chemotherapy as adjuvant therapy. In and after September 1994, she developed loco-regional recurrences five times in total, each of which was treated with surgery and conventional combination chemotherapy. In April 1997, she developed liver metastasis, which was refractory to biochemical modulation therapy (low-dose cisplatin + 5-FU). We, therefore, treated her six times with docetaxel 80 mg, which resulted in partial response of the liver metastasis and brought about a marked decrease in serum CA15-3 levels. Adverse effects of docetaxel were grade 3 alopecia and leucocytopenia. She has been well without re-growth of the liver metastasis for over five months.

MR-20 was administered to 52 gynecological cancer patients who presented with nephrotoxicity from cisplatin (CDDP) treatment over 3 courses at 33 institutions throughout Japan during the period from July 1992 through March 1994, in order to study its suppressive effect on the nephrotoxicity as well as its safety; and the results are reported in this paper.

As compared to the conventional standard chemotherapy of solid cancer such as lung, biochemical modulation (BCM) therapy has been proven to have a good therapeutic efficiency. BCM therapy uses the low dose and low infusion rate of anti-cancer drug. To increase of the QOL of cancer patients, oral BCM therapy is needed. For this purpose, two kinds of new oral sustained-release cisplatin preparations were developed, micro-porous CDDP capsule made of ethylcellulose(EC) and CDDP-EC-stearic acid solid dispersion. After oral administrations of these preparations, serum CDDP levels were maintained over 0.2 microgram/ml for 24h. Experimental therapy using P815 tumor cells transplanted mice suggested the usefulness of CDDP solid dispersion preparation.

Monolithic microcapsules were designed and developed for controlled release of leuprorelin for one month following a single injection. Copoly (DL-lactic/glycolic) acid (PLGA) of copolymer ratio of 75/25 and average molecular weight of 14,000 was suitable for achieving steady serum leuprorelin levels in rats and dogs for 4 weeks. The clinical efficacy of these injectable microcapsules of leuprorelin has been widely proved for prostate cancer, endometriosis, and other sex hormone dependent diseases in about sixty countries. The interaction between the basic functional group of the drug and the carboxylic end group of PLGA was found to be the most important factor in preparing the microcapsules with a small initial burst, as shown with thyrotropin releasing hormone (TRH) and a water-soluble GPIIb/IIIa antagonist (TAK-029).

Antitumor Prostaglandins such as delta 12PGJ2 and delta 7PGA1 possess a cross-conjugated dienone unit and exhibit unique antitumor effect. Lipid microshere (w/o type emulsion) was selected as pharmaceutical formulation because of physicochemical properties of prostaglandin. 13,14-Dihydro-15-deoxy-delta 7-PGA1 methyl ester (TEI-9826) were selected as a candidate for clinical trial. In a rat and mouse serum in vitro, TEI-9826 rapidly metabolized to 13,14-dihydro-15-deoxy-delta 7-PGA1 (TOK-4528), but TOK-4528 is stable as well as delta 12PGJ2. Lipid microshere containing TEI-9826 at the content of 5 mg/ml exhibited administration route and schedule dependent antitumor effect in vivo using Colon 26 bearing mouse model, which suggested that duration of serum concentration was important for antitumor effect. One of the antitumor mechanism of antitumor PG might be an induction of the cyclin-dependent kinase inhibitor p21. PPAR gamma also might be important. New type homogenizer, high pressure jet flow type homogenizer was developed in the study of antitumor prostaglandin.

For the purpose of intracellular targeting carrier by systemic administration, PEG-liposomes conjugating transferrin (TF) at the distal ends of PEG chain were newly prepared. Biodistribution of TF-PEG liposome was examined in the colon 26 bearing mice. TF-PEG liposome were prolonged in the circulation and highly accumulated into the tumor tissue. After extravasation, TF-PEG liposome retains the specific binding ability to tumor cell surface. Uptake of TF-PEG liposome was examined by electron microscopy. TF-PEG liposome was localized at the cell surface, coated pits and endosome. These results show TF-PEG liposome was bound and internalized by endocytosis. Such liposomes should be useful for intracellular targeting carrier at the way of systemic administration.

Organ level-targeting of anticancer drugs or other relating stimuli to tumor tissues and their circumstances is important in cancer therapy. The successful targeting results in the greater antitumor effect and the lower numerous side effects. Application of a magnet from the outside of body is a useful tool to increase the targeting efficacy. In this review paper, targeting technology utilizing magnetic microparticulate system for cancer therapy was introduced and the future on the magnetic targeting system was augured.

Clinical applications of monoclonal antibody for selective delivery of anticancer drug, toxin and radioisotope were reviewed. The difficulties in preparation and clinical application of chemoimmunoconjugate were pointed out. Also the difficulties of immunotoxin in clinical trial due to its high toxicity had been discussed and it is assumed that development of blocked ricin may overcome many problems related to toxicities. Clinically most advanced immunoconjugate seems to be radioimmunoconjugate. Among three types of immunoconjugates preparation of radioimmunoconjugate is easiest and some promising clinical trials were introduced in this review.

The current status of newly developed polyethyleneglycol coated liposome (PEG-liposome) were described in this review. Liposomes have demonstrated considerable promise as a carrier for the delivery of drugs in vivo. However, one of the drawback is that most liposomes intravenously injected into animals are rapidly removed from the blood circulation by uptake primarily in the cells of reticuloendothelial system (RES). It has been found that PEG-liposome are not readily taken up by the macrophages in the RES and hence stay in the circulation for a relatively long period of time. Pharmacokinetic analysis and therapeutic studies with tumor bearing mice revealed that PEG-liposomes have considerable potential as drug carriers for cancer therapy. Elevated liposome accumulation has been found in the tumor bearing mice model system. Results from clinical studies with doxorubicin encapsulated into PEG-liposomes (DOXIL) in AIDS-related Kaposi's sarcoma revealed an increased therapeutic efficacy compared to free-drug. These new formulations of long-circulating liposomes (PEG-liposome) offer the development of immunoliposomes with both long survival times in circulation and target recognition being retained in vivo. Fab'-PEG-immunoliposome was newly designed to gain long-circulating enough to extravasate to the targeted solid tumor in vivo. An ultimate goal of Fab'-PEG-immunoliposome is the incorporation of a fusogenic molecules that would induce fusion of liposome following their binding to the target cells or their internalization by endocytosis. Such liposomal formulations should be useful for endocytotic internalization of plasmid DNA and other bioactive materials.

It is reported that medroxyprogesterone acetate (MPA) causes venous thrombosis as one of the side effects. A 49-year-old woman suffering from metastatic lung carcinoma from breast carcinoma was administered MPA 1200 mg/day for about four months. Thereafter she complained of dizziness about two weeks but the general practitioners could detect no abnormality on physical examinations and on brain CT X-ray findings. Six days later, she died suddenly at her home. Forensic autopsy findings revealed the marked superior sagital sinus thrombosis and the malignant lymphadenomatosis caused by metastatic lung carcinoma. As the patient had not disease or trauma causing dural sinus thrombosis except for the administration of MPA, we concluded that superior sagital sinus thrombosis was due to the medication of MPA. This case illustrates that forensic pathologist should consider the major side effect of some drugs like our case.

Paclitaxel (Taxol) is a new class of anti-tumor agents which act by promoting the assembly and inhibiting the disassembly of microtubules. Single-agent studies have shown its significant activity for advanced cancers in various organs including ovary, lung, breast, and head and neck. Combination therapies with other anticancer agents have been extensively investigated in these cancers. Paclitaxel combined with cisplatin is now considered to be the standard treatment for advanced ovarian cancer. In other cancers, promising results have been obtained in several studies of paclitaxel-based chemotherapy. Major toxicities of paclitaxel-monotherapy are hypersensitivity reaction, neutropenia, and peripheral neuropathy. Combination of other cytotoxic agents sometimes leads to severer toxicities such as neurotoxicity with cisplatin and cardiotoxicity with anthracycline. Although further evaluation is needed, paclitaxel will be a main agent in the treatment of advanced solid tumors.

For patients with pulmo-mediastinal malignancies, the antimetic effect of granisetron was studied in the following two ways. Firstly in the standard method, 40 micrograms/kg of granisetron was infused for 30 minutes, 30 minutes before CDDP infusion. Secondly, in the simultaneous method, granisetron was mixed with CDDP in a 500 microliters infusion bottle, and then infused over 0.5-3 hours. Over a 24-hour time course, significantly effective rates (nausea less than mild, and vomiting 2 times less) were 72.7% in the simultaneous group (n = 22) and 52.6% in the standard group (n = 19). The non-effective rates were 18.2% and 15.8%, respectively. Although the results were not statistically significant, the simultaneous method is easier to perform and it seems to confer a slightly better clinical outcome than the conventional method.

Combined androgen blockade using a pure antiandrogen in association with a LHRH agonist or surgical castration is the most logical approach. This paper demonstrated that flutamide combined with leuprorelin acetate produced a significant reduction in the growth rate of Dunning R3327-H prostatic adenocarcinoma. Dunning R3327-H prostatic adenocarcinoma, provided by Dr. Norman H. Altmann (University of Miami, USA) was subcutaneously inoculated into the lateral region of male Copenhagen x Fischer F1 hybrid rat abdomen. The efficacy of the tumor growth rate was evaluated by measuring tumor size at 10 weeks after the inoculation. Flutamide was orally administered for 10 weeks and leuprorelin acetate was subcutaneously administered every 4 weeks. The effective dose of flutamide and leuprorelin acetate was determined in preliminary studies, and the following doses were used in the study; 15 mg/kg for flutamide, 0.1 mg/kg or 0.4 mg/kg for leuprorelin acetate. In combination of flutamide with leuprorelin acetate at 0.1 mg/kg and 0.4 mg/kg, the tumor inhibition was 94% and 97%, respectively. In addition, the weight of accessory sex organs coincided with the antitumor effect. Taking the above results into consideration, combined androgen blockade using flutamide and leuprorelin acetate may have some beneficial effect on prostatic cancer.

Tissue and serum concentrations of 5-fluorouracil (5-FU) after daily slow venous injection of tegafur or 5-FU for 5 days were measured. The serum concentration of 5-FU elevated to the highest level 6 hours after the venous injection (mean: 30 ng/ml). Compared with the tegafur injection, the serum concentration of 5-FU elevated to a higher peak level 6 hours after the 5-FU injection (mean: 827 ng/ml). The serum concentration of 5-FU after the tegafur injection tended to be maintained longer than after the 5-FU injection. When tegafur was injected, the concentration of 5-FU in cancer tissue or lymphnodes was significantly higher than in normal tissue. On the other hand, no significant difference was detected among the concentrations of 5-FU in the above three tissues when 5-FU was injected. Moreover, a significantly higher concentration of 5-FU in lymphnodes was caused by the tegafur injection compared to the 5-FU injection.

We evaluated the cytotoxic effects of mitomycin C (MMC) in rabbit eyes. A sponge soaked with MMC was placed on the bared sclera after conjunctival incision. We used four concentrations of MMC in distilled water: 0%, 0.04%, 0.1%, and 0.4%. MMC was applied to one eye only, with the fellow eye serving as control. The eyes were studied for intraocular pressure (IOP) and by fluorophotometry at 3, 7, 14, and 28 days of treatment. Eyes treated with 0.04% and 0.4% MMC were studied histologically at 3 and 28 days. All the MMC-treated eyes showed no significant changes regarding IOP (56 eyes) or fluorophotometric features (28 eyes) regarding aqueous humor dynamics and blood-aqueous barrier. Pathologic changes of the ciliary epithelium, including intracellular vacuoles and swelling of mitochondria, were more pronounced in eyes treated with 0.4% MMC than those treated with 0.04%. These changes were more manifest in areas inner to the site of application than in the opposite area. Topical application of 0.04% MMC thus showed no evident toxic effects on the function of the ciliary body and other pathological changes were minor.

We compared the effectiveness of treatments and the influence of side effects on liver function and clinical symptoms between segmental SMANCS/ Lip TAI and segmental SMANCS/Lip-TAE. The early tumor response rate of the group treated by TAI was 23.6%, and that of the group treated by TAE was 80.0%. In the group treated by TAE, the therapeutic effects were better in the nodular type than in the diffuse type of HCC, and we were also able to obtain a good tumor response rate on the multiple HCC and large HCC. However, there was no difference in the response period between the groups treated by TAI and TAE. In both groups, there were no significant differences in the appearance rate and degree of side effects. In conclusion, segmental SMANCS/Lip-TAE seemed to be an effective treatment for HCC without any serious complications.

Although intra-arterial infusion of SMANCS has been demonstrated to be highly effective for treatment of patients with hepatocellular carcinoma, it is reported to cause critical adverse reactions and complications. We examined the adverse reactions of SMANCS on the hepatic artery in 78 patients with hepatocellular carcinoma, who were infused with SMANCS from right, left or proper hepatic artery at our hospital. SMANCS caused right hepatic artery occlusion in 15 patients (19%) and the average amount of infused SMANCS was 6.8 mg. The tumor volume in the artery occluded patients was smaller than that in the artery non-occluded patients. Then, the mechanism by which SMANCS caused arterial occlusion was its induction of arterial injuries by excess infusion. When SMANCS was infused to whole liver, it induced decreased hepatic functional reserve and liver atrophy, followed by delayed liver failure. Other adverse reactions were no different from those in patients infused with epirubicin-lipiodol emulsion.

Twenty-four patients were treated with arterial infusion of SMANCS dissolved in Lipiodol. Twenty of these patients had HCC with the main trunks of portal vein occluded by tumor, and four patients had severe cirrhosis and multiple HCC. The actual dose of SMANCS administered each patient ranged from 4 to 6 mg. Side effects occurred in 50%. Severe side effects such as shock and shivering-chilliness were observed in 18%. The differences between the values of hepatic functional serum indexes obtained before and after treatment with SMANCS were small and transient. With regard to the therapeutic response of the arterial infusion of SMANCS, the mean survival time was approximately 2.8 months. It was suggested that the more effective administration of SMANCS was combination of the arterial infusion of SMANCS-Lipiodol with TAE at the level of the right hepatic artery of left hepatic artery for multiple HCC.