INCREASING THE EFFICIENCY OF PHOTOSENSITIZED DAMAGE OF EHRLICH ASCITES CARCINOMA CELLS USING HAEMATOPORPHYRIN DERIVATIVE OR CHLORIN-e6 IN COMBINATION WITH LONIDAMINE

Abstract

Lonidamine (a dichlorinated derivative of indazole-3-carboxylic acid) is an antispermatogenic and anticancer drug, which is believed to act as an inhibitor of energy metabolism. In this study the effect of lonidamine (LND) on the efficacy of photodynamic therapy of tumour was investigated. In in vitro experiments the presence of 0.25 mM LND increases synergistically (up to 2 fold) the intensity of hematoporphyrin derivative (HpD) or chlorin-eg trimethylester photosensitized damage of Ehrlich ascites carcinoma cells. Considerable inhibition of Ehrlich carcinoma rate growth in mice (the ascites form of tumour) was observed in vivo when HpD phototherapy (up to 5 mg/kg) was combined with LND (intraperitoneal injection of 0.1 mM/kg, before photoirradiation). The analysis of the interaction between LND and in vivo HpD photodynamic therapy demonstrated an additivity of response. The present effect of LND on the efficacy of phototherapy is mainly caused by the inhibitory effect of LND on the energy production system of tumour cells. Indeed, the increase of photodamage of tumour cells induced by LND was accompanied with an acceleration of the rate of decreasing their glycolytic activity and, at higher extent, oxygen consumption. We assume that the intensification of the reduction of the ATP content under photosensitization in the presence of LND was induced mainly by the inactivation of mitochondrion. Moreover, under hypoglycaemia neoplastic cells are more sensitive toward phototherapy combined with LND. We found that the mechanism ofthe potentiating effect of LND on HpD-phototherapy probably has a highly complex character. Thus, antineoplastic effect of LND and its combination with HpD-phototherapy is enhanced with increasing extracellular levels of calcium and magnesium cations. The results obtained indicate that the potentiating action of LND on phototherapy may be also explained by the injurious effect of LND on the cytoskeleton structure and cytoplasm membrane of tumour cells.

L-Buthionine-[S,r]-Sulfoximine May Enhance the Rate of Haematoporphyrin Derivative Photosensitized Inactivation of Tumour Cells Without Lowering the Intracellular Content of Glutathione

“…Indeed, a considerable inhibition of cellular respiration (Fig. 2), which was associated with a dramatic (approximately 80%) fall in the intracellular content of adenosine triphosphate [26], preceded the photodestruction of the outer membrane in the cells (Fig. 1).…”

“…We investigated the influence of L-BSO on the intensity of photodamage of EAC cells also in the presence of E6. Thanks to its better spectral properties, E 6 might be an alternative PS to HpD [26]. Moreover, E6, in contrast to HpD, is able to react in type 1 photoreactions [27].…”