Keith Chadwick Murdock

Relationship of chemical structures of anthraquinones with their effects on the suppression of immune responses.

A series of 37 anthraquinones were evaluated for their ability to inhibit the induction of cytolytic T-lymphocytes in a mixed lymphocyte culture system, useful as a preliminary screen for immunosuppressive agents. These compounds were also tested for their ability to prevent the production of antibody in mice. It was demonstrated that 1,4-bis [(2-aminoethyl)amino]-5, 8-dihydroxy-9,10-anthracenedione dihydrochloride (AEAD, 2) derived from mitoxantrone (MX, 1) by removing hydroxyethyl groups from both side chains was extremely active in depressing immune responses in vitro and in vivo. Four additional anthraquinones related to AEAD were also identified to share similar suppressive activity. They include a Schiff base, 1,4-dihydroxy-5,8-bis[[2-[(3-pyridinylmethylene)amino]ethyl]amino] -9,10-anthracenedione; a dimer with N-terminals methylated, 1,1-[ethylenebis (iminoethyleneimino)]-bis [5,8-dihydroxy-4-[(2-methylamino-ethyl)amino] anthraquinone tetrahydrochloride; an oxazolidine, 1,4-dihydroxy-5,8-bis [[2-(2-propyl-3-oxazolidinyl)ethyl]amino] anthraquinone; and its polymeric oxazolidine, poly [5,8-dihydroxy-1,4-anthraquinonyleneiminoethylene-3,2-oxazolidine- diyltrimethylene-2,3-oxazolidinediylethyleneimino]. These compounds may warrant further consideration as candidates for the treatment of refractory autoimmune diseases and in organ transplantation.

Chapter 14 Anti-neoplastic Agents

Publisher Summary Although the primary thrust of this chapter is to highlight the agents that act directly on tumor cells, other, more subtle areas of cancer research are evolving. The biochemical basis for cell differentiation has been discussed in the chapter, as well as the potential for chemotherapy with this approach. Retinoids, as anti-proliferative agents and inducers of differentiation and the early clinical experience with hexamethylene bisacetamide, have been discussed in the chapter. The biochemical rationale behind metastatic invasiveness is being elucidated. As knowledge of the process builds, drugs that hold promise as anti-metastatic agents are evolving. Two recombinant alpha-interferons have been granted food and drug administration (FDA) approval for clinical use against hairy cell leukemia. Numerous clinical trials for use of other interferons against cancer are in progress. Human trials are reported that used IL-2-activated autologous lymphocytes as well as high-dose IL-2 itself. Although objective responses are observed in both trials, the treatment is not without its critics because of its high cost and toxic side-effects. Tumor necrosis factor is also discussed in this chapter. As more monoclonal antibodies are developed that recognize tumor-associated antigens, the potential for passive immunotherapy increases, as does the possibility of active immunotherapy, either by vaccination with tumor antigens or through anti-ideotype responses.