RESUMEN
L-Proline-m-bis (2-chloroethyl) amino-L-phenylalanyl-L-norvaline ethyl ester hydrochloride (MF13) is a new anticancer tripeptide. Our previous study in vitro and in vivo showed that MF13 had anti-proliferative activities in a panel of human hepatocellular carcinoma (HCC) cell lines from different origin. In the present study, we focused on the inhibition effect on HCC of MF13 combined with other anti-cancer drugs. The results of combination chemotherapy in vitro indicated that the combination of MF13 with mitomycin C (MMC) at appropriate concentrations led to a synergistic effect; however, the combination of MF13 with vincristine (VCR) showed no synergistic effect. In the Bel-7402 tumor bearing nude mice, the antitumor effect of the groups of 2 mg·kg-1 MF13 + 2 mg·kg-1 MMC or 2 mg·kg-1 MF13 + 50 mg·kg-1 cyclophosphamide (CTX) exhibited synergistic anticancer efficacies while the group of 2 mg·kg-1 MF13 + 0.3 mg·kg-1 VCR did not have the same effect. Based on our data, we believe that MF13 can be considered as a potential agent against human hepatocellular carcinoma no matter how treated, alone or combined with other drugs.
RESUMEN
Aims: Brain and spinal cord tumors are the third most common type of childhood cancer following leukemia and lymphoma. Mechlorethamine (or mustine) is a nitrogen mustard antineoplastic drug. Eleven variants of mechlorethamine are presented that possess molecular properties enabling substantial access to tumors of the central nervous system. Study Design: An extensive in silico search within a data library of molecular structures identifieddrug scaffolds suitable for targeting brain tumors. Place and Duration of Study:University of Nebraska, Durham Science Center, Department of Chemistry, Omaha, Nebraska 68182 USA, between July 2012 to December 2012. Methodology: Following extensive in silico search and identification of potential drug structures, a conclusive set of brain penetrating structures were compiled. Extensive characterization of structure properties was accomplished followed by multivariate numerical analysis utilizing pattern recognition and statistical analysis. Results: All twelve compounds (including mechlorethamine) exhibited zero violations of Rule of 5, indicating favorable bioavailability. The range in Log P, formula weight, and polar surface area for these compounds are: 1.554 to 3.52, 156.06 to 324.12, and 3.238 A2to 22.24A2,respectively. High resolution hierarchical cluster analysis determined that agent 2 and 6 are most similar to the parent compound mechlorethamine. The average Log P, formula weight, polar surface area, and molecular volume are 2.446, 235.433, 8.58 A2, and 213.8 A3, respectively. Conclusion: These eleven drug designs possess attributes that effectuate high permeation into the central nervous system.
RESUMEN
Nitrogen mustards (HN) and sulphur mustard (SM) are potent alkylating blister inducing chemical warfare agents. Single 1.0 LD50 dose produced a progressive fall in body weight from second day onwards in all groups of mustard agents exposed animals. Histological examination of spleen, liver, skin and kidney revealed significant histopathological lesions in nitrogen mustards and sulphur mustard. These lesions include granulovascular degeneration with perinuclear clumping of the cytoplasm of hepatocytes and renal parenchymal cells. Renal lesions were characterized by congestion and hemorrhage. The maximum toxic manifestation were noted in spleen and skin of HN-3 exposed mice while sulphur mustard reported maximum toxicity in liver and kidneys. The study suggests both nitrogen mustards and sulphur mustard to be extremely toxic by percutaneous route based on histopathological observation and can contributed to earlier reported free radical generation by these toxicants.