Takeshi Okayasu

Inhibition of Catabolic Pathway of 5-Fluorouracil by 3-Cyano-2,6-dihydroxypyridine in Human Lung Cancer Tissues

Our studies of the degradation and the phosphorylation of S–fluorouracil (5–FU) in normal and tumor lung tissues from 10 cases of lung cancer have shown that the phosphorylation of 5–FU in the tumor tissues was about 2– to 3–fold higher than that in normal tissues, and that the degradation of 5–FU in tumor tissues was nearly 6–fold higher than that in normal tissues. BOF–A2 is an anti–neoplastic agent newly synthesized from l–ethoxymethyl–5–FU and 3–cyano–2,6–dihydroxypyridine (CNDP). The inhibitory effect of CNDP on the degradation of 5–FU in the tumor tissues was potent (IC50, 3.9 × 10−9M), Thus, BOF–A2 exerts its anti–neoplastic effect on tumors by potentiating the action of 5–FU through inhibition of 5–FU degradation by the CNDP moiety

The improved effects of specific active immunotherapy on a rat fibrosarcoma by antitumor drugs.

SummaryWe have tried to find out if the combination of a xenogenized tumor cell vaccine and antitumor drugs is able to induce a synergistic increase in the antitumor therapeutic effect. The degree of increase in the LTD50 (50% lethal tumor dose) is expressed numerically, as a quantitative index designed to compare degrees of transplantation resistance to tumor cell challenge. A LTD50 was achieved by an intradermal (i. d.) immunization with xenogenized tumor cells when challenged with tumor cells implanted intraperitoneally 2 weeks after the immunization: this LTD50 value was 527 000 times higher than that of the non-immunized group. When we combined this type of immunization with appropriate doses of bleomycin (BLM) or cyclophosphamide (CY), which are able to augment antitumor immunity, the LTD50 was 723 000–1190 000 times higher than that of the non-immunized group. This increase in the LTD50 is definitely higher than that achieved by a single immunization with irradiated tumor cells (× 33 000) and combined with either BLM (× 93 000) or CY (×140 000). We also studied the therapeutic effect of a tumor cell vaccine combined with antitumor drugs BLM or CY in tumor-bearing rats. We observed a synergistic effect caused by BLM or CY after i. d. immunization with xenogenized tumor cells: this showed a significant increase when compared with the therapeutic effects obtained by chemotherapy alone (P <0.01). Nevertheless, there was no evidence that the above antitumor effects is superior to the effect achieved by irradiated tumor cells.

Immunological regression of metastatic cancer in the liver as a result of "in vivo xenogenization"

We attempted to induce the regression of liver metastatic tumor cellsin vivo by the administration to rats of Friend leukemia virus (FV) (in vivo xenogenization). The virus which was used in this experiment, FV, is highly immunogenic and does not normally cause disease in an adult rat. At first, we induced a FV viremia in tumor bearing rats in order to deliver the virus to the site of the tumor cells. FV viremia was induced by injecting 60 mg/kg cyclophosphamide (CY) i.v. after the administration of FV, and by transferring syngeneic bone marrow cells so that FV would be able to infect them and then replicate.In order that the tumor cells which were infected with virus should regress, it was necessary to break down their tolerance to FV antigens. As adoptive immunotherapy we therefore, transferred syngeneic spleen cells from rats which had been immunized with FV to tumor bearing rats. The result of this experiment was that these tumor bearing rats infected with FV which had received either normal syngeneic spleen cells or no spleen cells as controls died from liver metastasis (8 out of 9 rats (89%) and 15 out of 17 (88%) respectively). On the other hand, only 4 out of the 15 (27%) tumor bearing rats which were infected with FV and which received FV-immune spleen cells died from liver metastasis.These sets of data indicate that thein vivo xenogenization of tumor cells are indeed able to induce the regression of metastic tumor cells.

Tumor Dormant States in Man

Tumor dormancy is a state in which lethal tumor cells persist under growth restraint in a clinically normal host for a prolonged period of time. Restraint on the tumor cell population may be either active, as a force which either arrests tumor cells at some stage in the cell cycle or which lyses them at the same rate at which they proliferate, or it may be passive, as in the absence of a factor which tumor cells require for proliferation, such as a hormone for hormone-dependent tumors or as essential nutrient in a vascular deficient tumor. The tumor dormant state is terminated by an event which results in either the destruction of all tumor cells, or the rapid increase in tumor cell numbers and development of a recurrent tumor.