Selective antitumor activity

According to a hypothesis launched by Larionov et al in the 1960s, some new nitrogen mustard derivatives were developed. They contain metabolites and heterocyclic structures as carriers of the cytotoxic chloroethylamine groups. By this way the synthesis of aliylating metabolites started melphalan (sarcolysine) as L- or DL-phenylalanine derivative prospidine with a tricyclic piperazine moiety and chlorambucil as butyric acid derivative. It was proven that each alkylating metabolite has its own spectrum of selective antitumor activity. 

Di Paolo C, Willuda J, Kubetzko S, Lauffer I, Tschudi D, Waibel R, Pluckthun A, Stahel RA, Zangemeister-Wittke U. A recombinant immunotoxin derived from a humanized epithelial cell adhesion molecule-specific single-chain antibody fragment has potent and selective antitumor activity. Clin Cancer Res 2003 9 2837-48. 

A brominated pyrrole-imidazole alkaloid, rac-dibromophakellstatin, has been shown to display selective antitumor activity in vitro with the highest activity on the ovarian cancer cell line OVXF 899L <2007BMCL346>. The chemistry and bioactivity of anti-tubulin agents, either natural or synthetic, having an indole as core nucleus have been reviewed <2007MI209>. 

The discovery of Taxol is a fruit of a National Cancer Institute (NCI)-sponsored project on identification of antitumor agents from natural resources. Bioassay-guided fractionation led to the isolation of this unique compound from Taxus bre-vifolia (pacific yew). Wani et al. also identified another famous antitumor natural product camptothecin. Unlike camptothecin, which was abandoned in the phase of clinical trial because of its severe toxicity, Taxol was almost discarded at the preliminary phase because it only exhibited moderate in vitro activity toward P388, a murine leukemia cell line that was used in the standard evaluation system by NCI researchers at that time. However, it was rescued by a subsequent finding of its strong and selective antitumor activities toward several solid tumors, and more... 

Drees M, Dengler WA, Roth T, Labonte H, Mayo J, et al. 1997. Flavopiridol (L86-8275) selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells. Clin. Cancer Res. 3 273-79... 

Francisco JA, Cerveny CG, Meyer DL, et al. cAClO-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 102 1458-1465. 

German investigators (Brock et al) worked on the creation of alkylating pro-drugs that have cytostatic activity after specific biotransformation in the tumor tissue. Cyclophosphamide (CTX) has well pronounced antitumor activity with the broadest spectrum. It is metabolized to the cytotoxic phosphoamide mustard. In normal tissues with high enzyme level cyclophosphamide is converted to its inactive metabolites (Fig. 2). These differences in biotransformation can explain the relative selectivity of cyclophosphamide towards... 

Table 6.4 Cytotoxcitiy and antitumor activity of selected gold complexes on B16 Melanocytes and P388 leukocyte. Adapted from Shaw [17].

Selective bioreductive alkylation in high DT-diaphorase cancer types (melanoma renal and nonsmall-cell lung cancers)15 would exhibit maximal antitumor activity with minimal side effects. 

Qui L, Kelso MJ, Hansen C, West ML, Fairlie DP, Parson PG (1999) Antitumor activity in vitro and in vivo of selective differentiating agents containing hydroxamate. Br J Cancer 80 1252—1258 Rea S, Eisenhaber F, O Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, AlUs CD, Jenuwein T (2000) Regulation of chromatin structure by site-specific histone H3 methyl-... 

Qiu L, Kelso MJ, Hansen C, West ML, Fairlie DP, Parsons PG. (1999) Antitumor activity in vitro and in vivo of selective differentiating agents containing hydroxamate. Br J Cancer 80 1252-1258. 

Comparative Antitumor Activity of Selected 4-Deacetyl vinblastine Amides against Several Murine Tumor Models... 

Jones, P. et al. (2008) A novel series of potent and selective ketone histone deacetylase inhibitors with antitumor activity in vivo. Journal of Medicinal Chemistry, 51, 2350-2353. 

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