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Reply

Department of Experimental Medicine, University of L’Aquila, 67100 L’Aquila, Italy

ABSTRACT

I thank Dr. O. Kaplan for his interesting comment on the study by Fanciulli et al.(1) published in Clinical Cancer Research.

Dr. Kaplan suggests that the lower extracellular content of lactate in LND¹-treated cells should be ascribed to an impairment of lactate transport with intracellular acidification rather than to the inhibition of glycolysis by affecting mitochondria-bound hexokinase. Nevertheless, we still believe that LND lowers extracellular lactate by inhibiting glycolysis.

The concentration of LND used in the nuclear magnetic resonance experiments cited by Dr. Kaplan (2) was much higher than that used in our studies (0.62 versus 0.2 mM). LND is a lipotropic agent, and it has been shown that LND is partitioned between membrane and the incubation medium, inducing a remarkable concentration-dependent effect on membrane ultrastructure and composition (3 , 4) . At LND concentrations higher than 0.3 mM, e.g., 0.4–0.8 mM, there is a massive loss of phospholipids, therefore, at 0.62 mM LND may impair not only bound hexokinase but carrier-mediated lactate transport as well.

Moreover, if LND was acting only on lactate transport, a greater intracellular content of lactate with higher acidification should have been observed in LND-treated Adriamycin-resistant MCF-7 cells due to their enhanced glycolysis. Instead, nuclear magnetic resonance studies (5) on these cells show a very low intracellular lactate accumulation, with only slight intracellular acidification when compared with LND-treated sensitive MCF-7 cells.

Furthermore, an effect on lactate transport should be excluded because LND at concentrations ranging between 0.15 and 0.30 mM stimulates aerobic lactate production in normal cells as well as in tumours of low malignant potential (6 , 7) , in which hexokinase is, for the most part, in cytoplasmatic form (8) .

Further direct evidence for mitochondria-bound hexokinase being the main target for LND comes from the study of Oudard et al. (9) on human gliomas transplanted in nude mice. In these studies, in vivo administration of LND leads to a significant (twofold) growth retardation only in those tumours with an elevated mitochondria-bound hexokinase activity, whereas no correlation was found between cytosolic hexokinase and growth inhibition.

FOOTNOTES

¹ The abbreviation used is: LND, lonidamine.

Received 7/21/00; accepted 7/26/00.

REFERENCES

1. Fanciulli M., Bruno T., Gentile F. P., Di Padova M., Rubiu O., Floridi A. Energy metabolism of human LoVo colon carcinoma cells: correlation to drug resistance and influence of lonidamine. Clin. Cancer Res., 6: 1590-1597, 2000.[Abstract/Free Full Text]
2. Ben-Horin H., Tassini M., Vivi A., Navon G., Kaplan O. Mechanism of action of the antineoplastic drug lonidamine: ³¹P and ¹³C nuclear magnetic resonance studies. Cancer Res., 55: 2814-2821, 1995.[Abstract/Free Full Text]
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5. Vivi, A., Tassini, M., Navon, G., and Kaplan, O. Comparison of action of anti-neoplastic drug lonidamine between drug sensitive and multidrug resistant MCF-7 human breast cancer cells. In: Proceedings of the Third International Congress of the Magnetic Resonance Society, pp. 1699–1699. Nice, France: , 1995.
6. Floridi A., Paggi M. G., Marcante M. L., Silvestrini B., Caputo A., De Martino C. Lonidamine, a selective inhibitor of aerobic murine tumor cells. J. Natl. Cancer Inst., 66: 497-499, 1981.
7. Paggi, M. G., and Caputo, A. Clinical significance of a rearranged hexokinase isozyme expression in neoplastic phenotype: the astrocytoma model. In: F. Cimino, G. Birkmayer, et al. (eds.), Human Tumor Markers, pp. 869–881. Berlin: Walter de Gruyter & Co., 1987.
8. Pedersen P. L. Tumor mitochondria and bioenergetics of the cancer cells. Prog. Exp. Tumor Res., 22: 190-274, 1978.[Medline]
9. Oudard S., Poirson F., Miccoli L., Bourgeois Y., Vassault A., Poisson M., Magdelenat H., Dutrillaux B., Poupon M. F. Mitochondria-bound hexokinase as a target for therapy of malignant gliomas. Int. J. Cancer, 62: 216-222, 1995.[Medline]

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