Kazuo Kuretani

Antitumor activity of 1-alkylcarbamoyl derivatives of 5-fluorouracil in a variety of mouse tumors.

SummaryThe antitumor properties of 1-alkylcarbamoyl derivatives of 5-fluorouracil were examined in various mouse tumor systems to select promising compounds for clinical use. Almost all alkylcarbamoyl derivatives were active against various tumors when given by oral administration. Among them, 1-methyl, 1-ethyl, 1-isopropyl, 1-hexyl and 1-octyl carbamoyl derivatives of 5-fluorouracil were moderately or markedly active in six mouse tumor systems tested. However, 1-methyl, 1-ethyl, and 1-isopropyl carbamoyl derivatives were toxic to mice, though not lethal. As a result, 1-hexyl and 1-octyl carbamoyl derivatives were selected as the best candidates for antitumor agents in further study.

Antitumor activity of 3′, 5′-diesters of 5-fluoro-2′-deoxyuridine against murine leukemia L1210 cells

SummaryAntitumor activity of several 3′,5′-diesters of 5-fluoro-2′-deoxyuridine (FUdR) against L1210 leukemia cells following intraperitoneal administration was examined. Esters of FUdR with aromatic acid or aliphatic acid of longer chain length were markedly active. Their activities, with respect to ILS30, were as much as 100 times that of unesterified FUdR. 3′,5′-ditoluoyl FUdR also had an improved therapeutic effect: its therapeutic ratio was increased to 8.1, as against 2.0 for FUdR. On the other hand, 3′,5′-diesters of FUdR with aliphatic acid of shorter chain length do not appear to be as active as FUdR. The relationship between the antitumor activity and plasma levels has also been examined. After 3′,5′-diacetyl FUdR, which is one of the drug group showing low cytotoxicity, the plasma concentration rapidly decreased to unmeasurable level 3 h after dosing. This tendency is similar to that shown in FUdR. On the other hand, with 3′,5′-dipalmitoyl FUdR and 3′,5′-dibenzoyl FUdR, each of which has a marked antitumor effect, plasma concentrations decreased slowly and were maintained for as long as 48 h after dosing. The results show that the cytotoxicity of diesters of FUdR is correlated with the duration of a high plasma level of FUdR.

Pharmacokinetics of 1-alkylcarbamoyl-5-fluorouracils in plasma and ascites fluid after oral administration in mice.

SummaryPharmacokinetics of 1-alkylcarbamoyl-5-fluorouracils was examined in mice bearing sarcoma 180. The alkylcarbamoyl derivatives were absorbed rapidly as intact form through the gastrointestinal tract and distributed into ascites fluid. Concentration-x-time (C-x-t) values of 5-fluorouracil formed in plasma and ascites fluid decreased in order by extension of the carbon chain of the alkyl moiety. C-x-t value of 5-fluorouracil formed in ascites fluid after hexylcarbamoyl derivative was higher than that in plasma. Antitumor activity of the compounds was correlated with both maximum concentration (Cmax) and C-x-t values of 5-fluorouracil formed and Cmax of total (intact form plus 5-fluorouracil formed) in ascites fluid (P<0.01), and with C-x-t values in ascites fluid and Cmax and C-x-t values of 5-fluorouracil formed in plasma (P<0.05). Alkylcarbamoyl structure was valuable for rapid absorption through the gastrointestinal tract and blood-ascites barrier and for maintenance of 5-fluorouracil level in plasma and ascites fluid.

EFFECT OF CENTROPHENOXINE ON CYCLOPHOSPHAMIDE CONCENTRATION IN BLOOD

In order to clarify the mechanism of potentiation of cyclophosphamide activity by centrophenoxine, blood concentration of total and activated cyclophosphamide was examined. Blood concentration of cyclophosphamide increased by the compound and biological half-life of activated cyclophosphamide was markedly increased to 30 min from 18 min in intraperitoneal administration. At the same time, concentration of active form in ascites fluid was also increased and biological half-life of the active form was increased to 50 min from 18 min. Similar increase in blood level of active form was also shown by p-chlorophenoxyacetic acid and probenecid, but concentrations at early stages after injection was not increased. As a result, potentiation of cyclophosphamide activity by centrophenoxine was found to be due to maintenance of active form in both blood and ascites fluid at higher levels than those in the control.

ACTION OF 5-FLUOROCYCLOCYTIDINE ON CULTURED L-5178Y CELLS

Effect of substitution of 5-position of cyclocytidine with fluorine on its antitumor activity in cultured cells was examined. 5-Fluorocyclocytidine was active against cultured L-5178Y cells similar to cyclocytidine. IC50 of the compound was 0.054 mug/ml. This compound inhibited thymidine incorporation into acid-soluble fraction of the cells. Cell growth inhibition by 5-fluorocyclocytidine was reversed by deoxycytidine but not by thymidine and deoxyuridine. On the other hand, cell growth inhibition by 5-fluorouracil was reversed by thymidine and deoxyuridine. As a result, site of action of 5-fluorocyclocytidine was considered to be similar to that of cyclocytidine and not to 5-fluorouracil.

Effect of Terephthalic Acid on Plasma Thiamine Level

テレフタール酸(TPA)を添加した飼料を与えると,血漿内チアミン濃度増加が促進されることがわかつたので,飼料への添加量を段階的に減らし,チアミン濃度の増加がどうかわるかをしらべた.80羽のニワトリ(ホワイトコーニッシュ(♀)とニユーハンプシヤー(♂)の交配種)を用い,チアミン塩酸塩(1mg/kg)を投与した後,6時間目の血漿内濃度を定量した.TPA群におけるチアミン濃度の増加は,0.1,0.2および0.4%群において,対照群の3.2,2.2および3.3倍の増加がみられた.その結果,ニワトリでは,血漿内チアミン濃度の増加を促進するためには,TPAを0.1%添加することで,充分効果が期待できるものと思われる.更に,TPAを添加した飼料を与えると,それだけで血漿内チアミン濃度が変化することがわかつた.0.1%群では増加し,0.4%群では,減少を示した.この0.4%群での血漿内濃度の減少は,投与チアミンによる血漿内濃度増加が促進されることからみて,消化管からの吸収が抑制された結果と考えるよりも,体内でのチアミン消費が増加したためか,あるいは,臓器内蓄積が増加した結果として起るものと考えられる

Effect of Irradiation on Lactating Animals

γ線照射の影響が,被照射動物及びその泌乳機能にどのようにあらわれるかを知るために,授乳5日目の母親に(仔は別にして)γ線を照射し母親体重,乳仔の体重の変化をしらべた.仔の生長に対しては,200r照射では影響がなかつた.400r以上では線量の増加にともない抑制がみられ800rでは増加率が対照に比べ10日目に140%減少している。又母親の体重はすでに200rで一時的な減少を示している.しかしこの線量では再び正常に回復する.一方800r照射は減少が急激であり4-10日で死亡する.400,600rでは減少,増加,減少と一時的な回復像がみられる.仔の死亡は母親の死亡に続いて起る.これらのことからγ線の作用では,母体の防禦機能を阻害する作用の方が乳腺の泌乳機能を阻害する作用よりも強いことがわかつた.又全身照射では800rでも仔の体重が増加していることから泌乳は継続することがわかつた.