THNLA-1: a DNA-targeted bioreductive agent as chemosensitizer in vitro and in vivo.

Abstract

THNLA-1 is a recently synthesized 2-nitroimidazole based, DNA-affinic bioreductive agent. It features a tetrahydroacridinic chromophore, which allows loose binding to DNA and therefore greater mobility along its backbone. THNLA-1 was proved to be a very good radiosensitizer and cytotoxin of hypoxic cells in vitro with an improved therapeutic index compared to the fully aromatic analog NLA-1. In this report we investigated the interaction of THNLA-1 with cis-DDP or L-PAM in the sensitive V79 and resistant OVCAR cells, using various schedule protocols. Also, the THNLA-1/cis-DDP interaction in balb/c mice has been investigated, using the EMT-6 mouse tumors. Isobologramic as well as fractional product concept analysis, clearly showed that synergistic interaction occurs between THNLA-1 and each chemotherapeutic agent, under hypoxic pretreatment conditions of the cells with THNLA-1 in vitro. The dose modification factor (DMF) values obtained in the resistant OVCAR-3 cells are similar to those obtained for the approximately 4 times more sensitive V79 cells. Therefore, the DMF value for e.g. L-PAM at 0.1 survival fraction, is approximately 2.76 when 15 microM THNLA-1 was used in OVCAR-3 cells, and approximately 2.50, when 10 microM THNLA-1 was used in V79. The supra-additive effect is dependent on the hypoxia-pretreatment time with THNLA-1, on THNLA-1 concentration and on the concentration of the chemotherapeutic drug. The limited in vivo study showed that THNLA-1, at doses significantly lower than its MTD, strongly potentiates the killing effect of cis-DDP and that the optimum effect during the combination treatment was observed when THNLA-1 was administered i.p., 2.5-3.0 h before cis-DDP. Toxicity studies in balb/c mice (without tumors) showed that THNLA-1 is well tolerated up to at least 70 mg/kg for more than 40 days while no toxicity was observed with the combined drugs used in our experimental protocol. These results are promising for the potential clinical use of THNLA-1 as an adjuvant in chemotherapy.

• Authors: M V Papadopoulou, M Ji, W D Bloomer
• Journal: In vivo (Athens, Greece) (In Vivo) 1996 Jan-Feb Vol. 10 Issue 1 Pg. 49-57 ISSN: 0258-851X [Print] Greece
• PMID: 8726811 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Alkylating
• Radiation-Sensitizing Agents
• 9-(3-(2-nitro-1-imidazolyl)propylamino)-1,2,3,4-tetrahydroacridine
• Tacrine
• DNA
• Cisplatin
• Melphalan

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Cell Hypoxia
• Cell Line
• Cell Survival
• Cisplatin (pharmacology)
• Cricetinae
• DNA (drug effects)
• Drug Interactions
• Female
• Melphalan (pharmacology)
• Mice
• Mice, Inbred BALB C
• Molecular Structure
• Radiation-Sensitizing Agents (pharmacology, toxicity)
• Tacrine (analogs & derivatives, pharmacology, toxicity)
• Time Factors
• Tumor Cells, Cultured