THNLA-1: a DNA-targeted bioreductive agent as chemosensitizer in vitro and in vivo.
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.
Papadopoulou
M V
MV
Evanston Hospital Corp., Department of Radiation Medicine, IL 60201, USA.
Ji
M
M
Bloomer
W D
WD
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D006224:Cricetinae; D004247:DNA / Q000187:drug effects*; D004347:Drug Interactions; D005260:Female; D008558:Melphalan / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000633:toxicity; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D013997:Time Factors; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D011838:Radiation-Sensitizing Agents; C092966:9-(3-(2-nitro-1-imidazolyl)propylamino)-1,2,3,4-tetrahydroacridine; D013619:Tacrine; D004247:DNA; D002945:Cisplatin; D008558:Melphalan