Murine, preparation

K Peters, S Leitzke, SE Diederichs, K Borner, H Hahn, RE Muller, S Ehlers. Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection. J Antimicrobial Chemother 45(l) 77-83,2000. 

Ghetie, V., Ghetie, M.-A., Uhr, J.W., and Vitetta, E.S. (1988) Large scale preparation of immunotoxins constructed with the Fab fragment of IgGl murine monoclonal antibodies and chemically deglyco-sylated ricin A chain./. Immunol. Meth. 112, 267-277. 

The antibody preparations could be administered unaltered or (more commonly) after their conjugation to radioisotopes or toxins. Binding of unaltered monoclonal antibodies to a tumour surface alone should facilitate increased destruction of tumour cells (Figure 13.4). This approach, however, has yielded disappointing results, as the monoclonal antibody preparations used to date have been murine in origin. The Fc region of such mouse antibodies is a very poor activator of human immune function. Technical advances, allowing the production of human/humanized monoclonals (see later) may render this therapeutic approach more attractive in the future. 

Figure 13.5 Outline of the production strategy of CEA-SCAN. The antibody-producing hybridoma cell line was originally obtained by standard methods of hybridoma generation. Spleen-derived murine B-lymphocytes were fused with murine myeloma calls. The resulting stable hybridomas were screened for the production of anti-CEA monoclonals. The clone chosen produces an IgG anti-CEA antibody. Note that the finished product outlined above is not radiolabelled. The freeze-dried antibody preparation (which has a shelf life of 2 years at 2-8 °C) is reconstituted immediately prior to its medical use. The reconstituting solution contains 99mTc, and is formulated to facilitate direct conjugation of the radiolabel to the antibody fragment...

Despite the scientific elegance of the antibody-mediated approach to tumour detection/destruc-tion, initial clinical trials proved disappointing. A number of factors contributed to their poor therapeutic performance, particularly against solid tumours. Most such factors relate directly/ indirectly to the fact that the first generation of such drugs utilized whole monoclonal antibody preparations of murine origin. These factors include ... 

Since natural product cryptolepine hydrochloride 173 (Fig. 48) has been found to be cytotoxic to B16 melanoma cells with an IC50 of 0.3 pg/mL (1.3 pM) [102], there has also been interest in cationic 5-carboline-based compounds as antitumor agents. For example, Wright and coworkers synthesized a series of these compounds and evaluated their activity against MAC 15 cells (murine adenocarcinomas of the colon) [103]. Of the compounds prepared, the most active was 179 which had an IC50 value of 1.03 pM. 

FIGURE 7.5 7,8-BPQ increases intracellular Ca2+ in murine spleen cells (A) and in both B and T cells (B). Single cell suspensions were prepared from murine spleens. Splenocytes were loaded with Fluo-3/AM dye for one hour and then treated with 7,8-BPQ, 1,6-BPQ, 3,6-BPQ, or DMSO (control). Surface-marker-defined T cells and B cells were treated with 7,8-BPQ or DMSO. Following treatment, the immediate intracellular Ca2+ response was continuously monitored for 15 minutes. Results are shown as the change in Mean Channel Fluorescence SEM. The numbers shown in this figure were the averages of triplicate determinants. Adapted from Gao et al., 2005. 

Rininger, J.A. et al., Immunopharmacological activity of Echinacea preparations following simulated digestion on murine macrophages and human peripheral blood mononuclear cells, J Leukoc Biol, 68, 503, 2000. 

An excellent antineoplastic potency against the murine neoplasm Sarcoma 180 has been observed with arylsulphonylhydrazones derived from pyridazine-3-carboxaldehyde 2-oxide (85) [298]. These compounds were prepared in the U.S.A. in order to investigate the effect of the incorporation of an additional nitrogen atom into antitumour active pyridine 1-oxide congeners. Interestingly, the pyridazine-derived compounds (85, R = H, Me, MeO) proved to be superior to the corresponding pyridine derivatives, whereas the analogous pyrimidine-4-carboxaldehyde 3-oxide derivatives were found to be devoid of activity. 

Mayer LD, Bally MB, Loughrey H, Masin D, Cullis PR. Liposomal vincristine preparations which exhibit decreased drug toxicity and increased activity against murine L1210 and P388 tumors. Cancer Res 1990 50 575. 

Although ciclosporin and tacrolimus applied systemically improve psoriatic lesions, they are clearly less active when applied topically. Therefore, liposomal preparations have been developed. Indeed, ciclosporin penetrates deeper strata of rodent and human cadaver skin more efficiently when incorporated into liposomes [51], Moreover, tacrolimus concentrations in murine skin have increased ninefold, and skin graft survival prolonged, if the drug is liposome encapsulated [52]. This indicates that topical psoriasis therapy with tacrolimus may become possible. At present, topical tacrolimus is confined to the less recalcitrant forms of mild eczema. 

Posner and coworkers have recently reported on the preparation of a number of orally active trioxane dimers with high stability and efficacy. In only a few chemical steps from naturally occurring artemisinin they are able to synthesize a number of compounds that show potent activity in an in vivo murine model of prostate cancer. 

Contraindications Concurrent use of immunosuppressive agents, hypersensitivity to any murine or humanized monoclonal antibody preparation... 

The therapeutic efficacy of either systemic or local pulmonary delivery of the IFN-y gene was evaluated in a murine allergen-induced airway hyperresponsiveness (AHR) model (Dow et al. 1999) and it was found that a high efficiency of gene transfer could be achieved. Intratracheal administered cationic liposomes were prepared from a mixture of l,2-diacylglycero-3-ethylphosphocholine (EDMPC) and cholesterol. Intravenous injections were prepared from l,2-dioleyl-3-trimethylammo-ninm propane (DOTAP) and cholesterol and compared with pulmonary administered... 

Parr et al. [61] showed that lipid A has the same antitumoral effect as whole endotoxin preparations on murine L5178Y lymphoma. The effects of LPS and synthetic lipid A treatments were compared by Shimizu et al. [158-161] on Meth A fibrosarcoma in BALB/c mouse. The antitumoral activity of different lipids A has also been investigated. Ribi et al. [162] used an extract from S. typhimurium containing lipid A, which when injected directly into hepatocarcinoma line 10 tumors in guinea pigs shows an antitumoral effect. This activity is attributed to a monophosphoryl diglucosamine derivative of lipid A [163], Synthetic lipid A analogs also proved to be active in this system [164], as well as... 

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