Pyrrolo[2,1-c][1,4]benzodiazepine and indole conjugate (IN6CPBD) has better efficacy and superior safety than the mother compound DC-81 in suppressing the growth of established melanoma in vivo.
Melanoma is one of the most chemo-resistant cancers. The remission rate of current therapy remains low. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of antitumor antibiotics that binds to N2 of guanine to form a DNA adduct. However, significant cardiotoxicity hampers their clinical use. We have previously synthesized a PBD indole conjugate (IN6CPBD) that induced apoptosis in several cancer cell lines. The purpose of this study was to assess the efficacy and safety of the IN6CPBD for established murine melanoma cells in vivo. IN6CPBD induced more apoptosis than DC-81 as evidenced by sub-G1 distribution, annexin V positivity, and decrease mitochondrial membrane potential (DeltaPsi(mt)). The melanomas were established in C57BL/6 mice by injecting B16F10 cells via the tail vein. Three courses of therapy were instituted after day 5 and the mice were sacrificed at day 20. The tumor growth rate in the foot pad was significantly reduced in IN6CPBD-treated mice than that in DC-81- and PBS-treated mice. The tumor burden in the lungs was also reduced significantly in IN6CPBD-treated mice accompanied with the most prominent TUNEL staining. Renal function, and cardiac enzymes were not altered significantly by IN6CPBD or DC-81, however, robust deterioration of liver function was noticed in the DC-81-treated mice. In summary, potent apoptosis could be elicited by the PBD indole conjugate IN6CPBD, accompanied with a better efficacy and less liver function impairment than the mother compound DC-81 in treating established melanoma metastasis in vivo.
Department of Dermatology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Chih-Hung
CH
Lee
Wan-Ping
WP
Hu
Chien-Hui
CH
Hong
Hsin-Su
HS
Yu
Wei-Ting
WT
Liao
Chung-Yu
CY
Chen
Yeh-Long
YL
Chen
Bai-Hsiun
BH
Chen
Gwo-Shing
GS
Chen
Jeh-Jeng
JJ
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis; D001381:Azepines / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D001569:Benzodiazepines / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy*; D014183:Transplantation, Heterologous
C474072:(11aS)-8-hydroxy-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5-one; D000970:Antineoplastic Agents; D001381:Azepines; C523952:IN6CPBD; D007211:Indoles; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D001569:Benzodiazepines