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Anticancer drugs are traditionally classified either by their mechanism of action or by their origins. Alkylating agents are reactive to DNA and cellular proteins and the primary mode of action is mostly through cross-linking of DNA strands, inhibiting replication of DNA and transcription of RNA. Some antimetabolites are structural analogs of normal molecular essentials for cell growth. After intaking into cells the analogues change to substances to interfere with DNA or RNA synthesis. Drugs derived from microorganism are called antitumor antibiotics. Some plants alkaloids blind to tublin and inhibit the formation of microtubules causing metaphase arrest, while camptothecins inhibit topoisomelase 1. Other compounds which are not classified to any categories expects characteristic mode for action to induce cell death or differentiation.

The antitumor activity of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl) cytosine (ECyd) and 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl) uracil (EUrd), designed as a potential multifunctional antitumor nucleoside to inhibit RNA and DNA syntheses, was examined. ECyd and EUrd inhibited the growth of 47 kinds of cultured human cells in vitro and also showed strong antitumor effects on 15 human solid cancers xenografted into nude mice at a dose of 0.25 mg/kg (ECyd) or 2 mg/kg (EUrd) by intravenous administration for 10 consecutive days. The in vitro cytotoxic effect of ECyd and EUrd was prevented dose dependently by cytidine and uridine, suggesting that ECyd and EUrd may require phosphorylation by uridine/cytidine kinase for antitumor activity. ECyd and EUrd strongly inhibited RNA synthesis and slightly inhibited DNA synthesis. ECyd and EUrd have shown potent antitumor activity against human experimental solid type tumors with minimal toxic effects in vivo, suggesting that ECyd and EUrd is a promising agent with a unique mechanism of action for the treatment of cancer.

HO-221, N-[4-(5-Bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2-nitrobenzoyl ) urea is a novel benzoylphenylurea derivative. We previously reported HO-221 showed significant antitumor activities against various experimental tumor models, and was especially effective against the solid tumor. In this report we studied the mechanism of action of the compound. The inhibitory activity of HO-221 and 6 kinds of antitumor agents on DNA polymerase alpha was examined in vitro. HO-221 inhibited DNA polymerase alpha activity strongly. From the comparison with IC50 values of individual agents, the inhibitory activity of HO-221 was almost equivalent to aphidicolin and ara-CTP. By double reciprocal plot analysis, the inhibition of HO-221 was found to be non-competitive with the dCTP unlike that of aphidicolin and ara-CTP. Furthermore, HO-221 showed almost no effect on RNA polymerase activity and the protein synthesis. The effect of HO-221 on cell cycle progression of HL-60 cells was examined by flow cytometry analysis. The compound accumulated cells at S phase at a low concentration. The compound showed accumulation of cells in G1, G1-S and G2 + M phases. At higher concentrations, HO-221 increased the G1 phase of tumor cells, stopping the cell cycle progression. Therefore, G1 and S phase accumulation by HO-221 was considered to be correlated with the inhibition of DNA polymerase alpha dependent DNA synthesis. These results suggest that HO-221 is a novel antitumor agent with different mechanism of action from the known antitumor agents.

The effects of Medroxyprogesterone acetate (MPA) and progesterone (P) on DNA and RNA contents of a human endometrial cancer cell line (Ishikawa) and a human breast cancer cell line (MCF-7) were studied using Flow cytometry. The results were as follows. MPA and P at a high dose of 10(-5) M inhibited their cell cycle progression through the G1 phase or G1-S phase boundary and showed a decrease in the number of cells which underwent DNA synthesis and mitosis. P at a low dose of 10(-7) M showed the lengthening of cell cycle time in the S phase. MPA at 10(-7) M had an inhibitory effect on the cell cycle progression of Ishikawa cells similar to that of a high dose of MPA whereas, in the case of MCF-7 cells, it showed a lengthening of duration in the S phase. Therefore, the dose-responsibility of these cells to MPA were shown to be different. A high dose of MPA and P showed a decrease in the cytoplasmic and nuclear RNA contents. A low dose of MPA and P had no marked effect on the RNA contents. From these results, it was clarified that MPA, especially at a high dose, could substantially inhibit RNA synthesis and DNA synthesis with a delay of the cell cycle progression in hormone responsive cancer cells.

Mechanism of cytotoxicity of 5-fluorouracil (5-FU) in relation to impairment of RNA metabolism was studied. 5-FU depressed the levels of ribonucleotide reductase and thymidine kinase, which are two key enzymes in DNA synthesis, in solid AH-130 tumor when given intraperitoneally at a dose of 60 mg/kg, and this inhibition seemed to be very toxic against cells. But this dose of 5-FU exceeded the amount that could be degraded by the liver, which was much higher than the clinical dose. We concluded that the impairment of RNA metabolism caused by 5-FU played a minor role in its anti-tumor actions.

TNF is cytokine derived from macrophages and shows much promise for use in cancer therapy because of its marked antitumor effects and its high specificity to tumors. The clinical application (Phase I-II) of TNF has been started because human recombinant TNF (rH-TNF) can be produced on a large scale. In spite of notable antitumor effects, little is known concerning the mechanism of its cytotoxic action. In this article, the antitumor effects of rH-TNF against human and murine tumors, the mechanism of its action and the synergistic effects of rH-TNF in combination with IFN-gamma, various anticancer drugs or with hyperthermia are reviewed.

Since Kistner in 1959 took up the gestagen therapy for endometrial hyperplasia and endometrial carcinoma with a view to inhibiting cellular proliferation, many clinical reports on that therapy have been published. It has been clarified by cell-biological studies that progesterone inhibit the DNA synthesis of endometrial cells followed by the discontinuance of cell division. At dichophase , prior to the onset of the S-stage in cell division cycle, under conjugation of progesterone with a certain specific type of protein (hormone receptor) the cells are induced toward the development of secretory function, i.e. toward differentiation, resulting in no synthesis of DNA. On the basis of the consideration mentioned above, when hormone treatment will be applied to endometrial carcinoma it is required that those cancer cells have the gene activated by administered hormone or have specific type of protein produced by hormone dependent gene in cytoplasm. When cancer cells have still retained the traits of the normal epithelial cells of endometrium, they were believed still possess the character to show the specific reaction to progesterone. However, not all the cancer cells can be considered to have a uniform character (the degree of differentiation), so gestagen therapy cannot be interpreted to be able completely to bring about the fundamental cure of endometrial carcinoma.