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Uptake, Cytofluorescence, and Cytotoxicity of Oxazolopyridocarbazoles (Amino Acid-Ellipticine Conjugates) in Murine Sarcoma Cells¹

Laboratoire de Pharmacologie Moléculaire, Centre National de la Recherche Scientifique 147, and Groupe de Recherches sur la Pharmacologie de Médicaments Anticancéreux, Institut National de la Santé et de la Recherche Médicale 140, Institut Gustave-Roussy, 94805 Villejuif Cédex, France

The uptake, cytofluorescence, and cytotoxicity of elliptinium (NMHE) and a series of fluorescent oxazolopyridocarbazoles [amino acid-ellipticine conjugates (AA-NMHE)] were studied in murine sarcoma cells. For all these drugs, the uptake was rapid, directly proportional to the drug concentration, and unaffected by metabolic inhibitors which is consistent with a diffusion mechanism. By 4 h, the intracellular concentration of NMHE exceeded the external drug concentration by about 100 times; this suggests that the toxicity of NMHE is not, as previously assumed, limited by its transport across tumor cell membranes. Conjugation of NMHE with aliphatic amino acids increased the cellular uptake 5- to 7-fold. Cellular exposure to AA-NMHE conjugates resulted in the appearance of granular cytoplasmic fluorescence which was readily translocated to the nucleus upon continued exposure to fluorescent light. The cytotoxicity of the AA-NMHE conjugates (drug concentration required to reduce colony formation by 63% on the exponential part of the survival curve = 3–14 µM) was less than of NMHE (drug concentration required to reduce colony formation by 63% on the exponential part of the survival curve = 0.7 µM) as shown by colony formation following 4 h drug exposure. In contrast, the isoleucine-NMHE conjugate was the most cytotoxic compound (drug concentration required to reduce colony formation by 63% on the exponential part of the survival curve = 0.045 µM) when the drug exposure period was extended to 8 days. The general lower toxicity of the AA-NMHE conjugates is likely due to loss of the phenolic character of the NMHE moiety; therefore, attempts to link NMHE to amino acids remain attractive but will have to be done without affecting the 9-hydroxy group of NMHE.

¹ This work was supported by Association pour le Développement de la Recherche sur le Cancer, Villejuif, France.

² To whom requests for reprints should be addressed.

Received 3/24/86. Revised 6/25/86. Accepted 6/26/86.