To determine the significance of the proliferative activity of hepatocellular carcinoma (HCC), we studied the bromodeoxyuridine (BrdU) labeling index (L. I.) in 24 consecutive patients with HCC. The BrdU L. I. ranged from 0 to 17.8%, averaging 3.01±4.22% (mean ± SD). Conventional pathological features of HCC such as tumor size, intrahepatic metastasis, vascular involvement, were not correlated with the BrdU L. I. Multivariate analysis revealed that the BrdU L. I. was a significant predictor of the disease-free survival time.
Both the disease-free survival time and the survival rate of the low BrdU L. I. (>2%; n=12) group were significantly better than those of the high BrdU L. I. (>2%; n=7) group (p=0.0275 and 0.0462, respectively). All patients in the high BrdU L. I. group showed recurrence within 2.5 years compared with only 40% of the low BrdU group. In conclusion, measurement of the BrdU L. I. is a useful tool for the follow-up of HCC patients.

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Leucovorin (LV)•5-FU combination chemotherapy has been commonly used as adjuvant therapy for gastrointestinal cancer, which induces few side effects and has a high activity. Peritoneal dissemination frequently occurs after surgery and its prevention is essential for improving the prognosis of patients with gastric and colorectal cancer. Before applying LV•5-FU combination therapy for the treatment of peritoneal dissemination, it is necessary to develop the drug delivery systems capable of maintaining optimal concentrations in the peritoneal cavity. We created a slow-release LV microcapsules using liposomes and studied the therapeutic effect of liposome-encapsulated LV (LV liposomes) combined with 5-FU in a mouse model of peritoneal metastasis. LV liposomes demonstrated much more gradual drug release in the peritoneal cavity compared to free LV. In the model of peritoneal dissemination, both averaged tumor weight and the incidence of peritoneal metastasis were lower in the mice treated with LV liposomes and 5-FU than in animals given free LV and 5-FU (p=0.01). In conclusion, LV liposomes combined with 5-FU may be clinically useful for the prevention and treatment of peritoneal dissemination.

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Surface molecules such as HLA class 1, HLA-DR, intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-3 (LFA-3) on tumor cells play an important role in the immune system of cancer-bearing hosts. Interferon (IFN) gamma has been reported to have a variety of effects on cancer and immune cells. Specimens from gastric cancer (GC), colorectal cancer (CRC), and hepatocellular carcinoma (HCC) were studied. IFN gamma were locally administered into the tumors of some patients before surgical resection and the IFN gamma-treated groups were compared with the untreated groups. There was no expression of ICAM-1 by untreated HCC tumor cells, while, 75% of treated HCC tumor cells showed ICAM-1 expression. LFA-3 expression on cancer cells was increased by IFN gamma in CRC and HCC. The percentage of tumor-infiltrating lymphocytes (TIL) expressing CD3 and CD8 was higher in the IFN gamma-treated group than in the untreated control group in all these diseases. These findings suggest that host defense mechanisms were induced by preoperative intratumoral injection of IFN gamma and this change may result in better local control.

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We investigated the critical determinants of cytotoxic activity for cisplatin (CDDP), mitomycin C (MMC), and nimustine hydrochloride (ACNU), which are commonly used to treat malignant glioma. In 10 human cancer cell lines, glutathione S-transferase (GST) was a significant resistance factor for CDDP. MMC activity was found to be determined through the balance between activation by NADPH: quinone oxidoreductase (DTD) and inactivation by GST, while NADPH: cytochrome P450 reductase (P-450) was important in ACNU resistance. Two glioblastoma cell lines, T98G and U-251 MG, showed remarkably high levels of these 3 enzymes and glutathione (GSH), thus being moderately sensitive to MMC and resistant to CDDP and ACNU. Inhibition of these target enzymes caused an increase of the efficacy of each drug. KW2149, a novel MMC analogue activated by GSH, was active against T98G and U-251MG cells due to their high GSH levels. Molecular targeting to seek the best treatment modality or the most active drug may contribute to improving the effectiveness of glioma chemotherapy.

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Recent findings regarding abnormalities of the TGF-β receptor and loss of its responsiveness to TGF-β in tumor cells have suggested that this receptor is one of the tumor suppressor genes. Abnormalities of the intracellular signal transduction pathway for TGF-β in tumor cells have also been reported, to which the TGF-β receptor contributes. In order to clarify the tumor suppression mechanism involving the TGF-β receptor, it has become necessary to gain a comprehensive understanding of the series of abnormalities in the signal transduction pathway. In this paper, we discuss the TGF-β receptor and the relationship of cancer to these abnormalities in the signal transduction pathway.

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The survival rate of patients with malignant glioma is still low. Because of the existence of blood-brain barrier (BBB) and the blood-tumor barrier, the delivery of anticancer agents is limited in the central nervous system. To overcome this problem, establishment of new targets for anticancer therapy and new drug delivery systems is important. The expression of various vascular growth factors in human brain tumors was examined in this study. Vascular endothelial growth factor (VEGF) might be a new candidate for anti-glioma therapy because it is deeply involved in angiogenesis occurring in malignant gliomas. The properties of brain tumor capillaries with regard to BBB-specific structure and function were also investigated. Gliomas had relatively well preserved BBB structure and function in their capillary endothelial cells. To overcome the blood-tumor barrier and to establish a new drug delivery system, we examined the effects of intracarotid infusion of various vasoactive agents on regional blood flow and capillary permeability in normal and tumor tissue in an animal model. Intracarotid infusion of bradykinin seemed to be the most promising drug delivery system for glioma, making it possible to deliver various anticancer agents selectively to malignant gliomas. Combining these approaches may lead to more effective and selective anti-glioma therapy in the near future.

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Peritoneal metastasis after surgery is a critical prognostic factor in cancer patients. This type of recurrence is considered to originate from microscopic dissemination in the peritoneal cavity, and the eradication of such dissemination is necessary for the improvement of survival. We evaluated the preventive effect of intraperitoneal administration of macrophage colony-stimulating factor (M-CSF) and OK-432 on the development of peritoneal metastasis.
Intraperitoneal administration of M-CSF (1×10⁴U) and OK-432 (0.2KE) for 5 days significantly increased the number of peritoneal effusion cells and peritoneal macrophages as well as the cytotoxicity of the peritoneal macrophages when compared with M-CSF or OK-432 alone. In addition, the release of TNF-α and NO₂^- from macrophages was significantly increased by combined intraperitoneal administration of M-CSF and OK-432.
In a peritoneal metastasis model created by peritoneal inoculation of colon 26 cells into BALB/c mice (male, 6 weeks old), the combined intraperitoneal administration of M-CSF and OK-432 inhibited weight loss, reduced the intraperitoneal tumor weight, and prolonged the survival of mice as compared with M-CSF or OK-432 alone.
In conclusion, combined intraperitoneal immunotherapy with M-CSF and OK-432 may be useful for the treatment or prevention of peritoneal metastasis.

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The p16^INK4A gene encoding a cell cycle regulatory protein, cyclin-dependent kinase 4 inhibitor, is a putative tumor suppressor gene. We examined p16 gene alterations in 11 ovarian cancer cell lines. Three cell lines had homozygous deletion of p16, 1 cell line had multiple intragenic mutations, and there was suppressed transcription of the p16 gene in 1 cell line. Some point mutations were also found in the conserved ankyrin consensus. These observations suggest that abnormalities of p16 are related to ovarian carcinogenesis. We then investigated whether gene products directly or indirectly linked to the Rb-mediated negative regulation of the cell cycle might have been targeted for mutation, resulting in a phenotype resembling loss of p16 function in ovarian cancer cells. p16 protein was undetectable in 5 cell lines due to homozygous deletion, missense mutations of both p16 alleles, or transcriptional silencing. These 5 cell lines expressed Rb protein at detectable levels. In contrast, Rb protein was undetectable in 4 of the 6 cell lines that expressed detectable p16 protein. Thus, tumor cell lines expressing Rb protein rarely expressed p16 protein, and conversely p16 expressing tumor cell lines rarely had detectable levels of Rb protein. The high level of aberrant expression of Rb or p16 in ovarian cancer cell lines supports the concept that these proteins interact to form a critical cell cycle checkpoint, and that the suppression of Rb or p16 is sufficient to disrupt the regulatory mechanism in a manner that favors proliferation.

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