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KMID : 0379119870150030199
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Korean Journal of Mycology
1987 Volume.15 No. 3 p.199 ~ p.199
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Present Status and Perspectives of Cancer Chemotherapy to discover more potential antitumor agents
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Fujimoto, Shuichi
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Abstract
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In order to discover potential new antitumor agents, we should understand the backgrounds for refractoriness of a majority of human tumors towards chemotherapy. Three kinds of mechanisms for resistance, i. e., temporary, kinetic and inherent resistances, are introduced in the present paper.
Antitumor agents are classified into two groups with respect to modes for cytocidal action against tumor cells in vitro and in vivo. One is a cell-cycle-phase specific and the other is a cell-cycle-phase nonspecific(however, cycle specific). The former drugs show their cytocidal activity against tumor cells in a specific phase of the cell cycle. Antimetabolites and vinca alkaloids belong to this class. Thess drugs show logarithmic cytocidal action with increasing dose. After eradication of tumor cells in this specific phase, however, the remaining tumor cells in other phases are insensitive to these drugs, leading to the temporary resistance.
Rapidiy growing tumors have a relatively high sensitivity to antitumor agents. Clinically detectable tumor size is approximately 1 ㎝ or more in diameter, and this tumor mass contains approximately 1 × 10^9 cells(1g) and tumor cells already carried out 30 times cell division. On the other hand, tumor mass at terminal stage reaches 1 × 10^(12) cells(1 ㎏) or more, and they carry out further 10 times cell division. The tumor growth rate we refer is those between the tumor mass of lg and 1 ㎏. Majority of human solid tumors have slow growth rate, leading to the kinetic resistance.
Appearance of drug-resistant tumor cells is a serious obstacle to perform an effective chemotherapy, leading to the inherent resistance. It has been observed for a number of different tumor cells in culture that approximately 1 in 10^6(10^(-6)) cells of a given population is resistant to a given drug. Furthermore, most antitumor agents are variably mutagenic so that, during treatment, mutant daughter cells are produced that have a higher potential for being genetically drug-resistant. Several studies indicate that such chemical mutagens will increase the population of drug-resistant cells by a factor of 100. Therefore, treatment failure due to drug resistance may occur if the initial unexposed population of tumor cells is greater than 108 or if the number of daughter cells produced during treatment is greater than 10⁴. The clinical studies of new antitumor agents are carried out for those patients with tumors refractory to chemotherapy either initially or after treatment. Those tumor cells may show the pleiotropic cross resistance to new antitumor agents.
Taking these problems into consideration, a new device should be developed for discovering new antitumor agents from natural products as well as from synthetic compounds.
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