Promotive effects of hyperthermia on the сytostatic activity to ehrlich ascites tumor cells by diverse delta-alkyllactones

Tanaka H., Kageyama K., Asada R., Yoshimura N., Miwa N.

To evaluate promotive effects of hyperthermia on antitumor activity of new delta-alkyllactones (DALs) of low molecular weight (184–254 Da), chemically synthesized, which are different from natural macrocyclic lactones of high molecular weight (348–439 Da), such as camptothecin and sultriecin. Methods: A suspension of Ehrlich ascites tumor (EAT) cells was mixed with a DAL in a glass tube, heated at 37 or 42 °C for 30 min in a water bath, and cultured at 37 °C for 20 or 72 h. Cell viability was measured by the mitochondrial dehydrogenase- based WST-1 assay. DALs incorporated into EAT cells was extracted and measured by gas-liquid chromatography. Results: The reduction of cell viability by DALs was markedly enhanced upon the treatment at 42 °C compared to that at 37 oC. At 37 oC, delta-hexadecalactone (DH16 : 0) and delta-tetradecalactone (DTe14 : 0) displayed cytostatic activity (at 100 µM survival level: 20.7%, 66.1%; at 50 µM — 41.2%, 82.4%, respectively). Their activity was more marked at 42 °C (at 100 µM 10.6%, 27.6%; at 50 µM 30.6, 37.5 %, ibid). The other DALs, delta-undecalactone (DU11 : 0), delta-dodecalactone (DD12 : 0), and delta-tridecanolactone (DTr13 : 0) were almost ineffective. Evaluation of survival rate in the cells treated for 30 min by DALs with the next culturing of EAT cells for 72 h resulted in the enhanced carcinostatic activity of DH16:0 and DTe14:0 even at concentrations as low as 25 µM at either 37 °C (18.5%, 78.5%, ibid) or 42 °C (5.0%, 42.0%, ibid), but the others exhibited slight activity or none. DH16 : 0 was effective at either 37 °C (36.0%) or 42 °C (23.0%) even at a lower dose of 10 µM. At the same time only the most cytostatic DH16 : 0 was incorporated into EAT cells and the rate of incorporation was more at 42 °C than at 37 °C. Conclusion: Delta-hexadecanolactone (DH16 : 0) exhibited the most cytostatic effect that was significantly enhanced by hyperthermia. It allows to consider it as a potent antitumor agent, especially in combination with hyperthermia.

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