Lymphocyte antitumor activity

Interferons (lENs) (52,53), a family of species-specific vertebrate proteins, confer nonspecific resistance to a broad range of viral infections, affect cell proliferation, and modulate immune responses. AH three principal interferons, a-interferon (lEN-a) produced by blood leucocytes, P-interferon (lEN-P) by fibroblasts, and y-interferon (lEN-y) by lymphocytes, also have antiviral activity. The abiUty of interferons to inhibit growth of transplantable and carcinogen-induced tumor led to research showing the direct antiproliferative and indirect immune-mediated antitumor activities (see Chemotherapeutics, anticancer). IENs have been found to be efficacious in certain malignancies and viral infections, eg, hairy cell leukemia (85% response) and basal cell carcinoma (86% response). However, the interferons do have adverse side effects (54). 

Biological Activity. The maytansinoids possess antitumor activity, particulady against P 388 lymphocytic leukemia, B 16 melanocarcinoma, and Lewis lung carcinoma. A number of semisynthetic esters of maytansinol have been prepared and exhibit good antileukemic activity (52,255). The maytansides lack antitumor activity, indicating that the ester at C-3 is a requirement for activity (50,52). The carbinolamide also appears to be necessary for... 

Several cytokines are in clinical use that support immune responses, such as IL-2, DFNs, or colony-stimulating factors. IL-2 supports the proliferation and effector ftmction of T-lymphocytes in immune compromised patients such as after prolonged dialysis or HIV infection. IFNs support antiviral responses or antitumoral activities of phagocytes, NK cells, and cytotoxic T-lymphocytes. Colony-stimulatory factors enforce the formation of mature blood cells from progenitor cells, e.g., after chemo- or radiotherapy (G-CSF to generate neutrophils, TPO to generate platelets, EPO to generate erythrocytes). 

The electronic spectra and magnetic susceptibility of [Ni(21)Cl2] were found to be consistent with a five-coordinate high spin complex. This complex has greater antitumor activity against P388 lymphocytic leukemia test system in mice than cobalt(II), copper(II), zinc(II) and platinum(II) complexes of 21 [187],... 

The thiazoloimidazopyridine derivatives 451 were tested for their effect on human immunodeficiency virus (HIV)-induced cytopathogenicity in a human T4-lymphocyte cell line and showed a reproducible anti-HIV activity that caused a 50% or greater reduction of viral cytophatic effect <1994FA345>. Finally, imidazo[2,1 -/dthiazolone 489 was found to have an antitumor activity and proved to be effective against brain tumor cell lines <2002JHC1133>. 

Oxoleurosine (14) was evaluated for antitumor activity according to established protocols. No activity was observed in the dose range 0.25-6.25 mg/kg in the P388 lymphocytic leukemia system in mice, but the alkaloid was cytotoxic in the KB test system in vitro (EDjo 0.31 p.g/ml) (52). 

Many of the N-1 derivatives described above show antitumor activity. Compound 56 is active against P388 murine lymphocytic leukemia at a dose of 6.0 mg/kg/day x 8 (i.p.), giving an ILS of 82%, and compound 57 shows an improvement in the therapeutic index of vinblastine. Compound 58 was also active against P388 at very low doses (0.1 mg/kg/day... 

LPS can be directly mitogenic for T cells [130], but the antitumoral activity of lymphocytes depends on antigen recognition by their TCR in the context of the major histocompatibility complex (MHC) class I or n. Though LPS enhance it, T lymphocyte activity requires APC [131]. The effect of LPS on T lymphocytes has been shown to depend on monocytes independent of MHC, but to be due to the secretion of costimulatory signals and IL-12 in humans [132]. In vivo, LPS induces principally the proliferation of CD8+ T lymphocytes, but also that of CD4+ T and B lymphocytes through the activation of APC and secretion of IFN 0(7(3 in C57BL/6 mice [133],... 

Interferons. The interferons (IFNs),196,197 which were discovered in 1957, are proteins secreted by leukocytes, fibroblasts, and activated lymphocytes. They inhibit replication of viruses as well as the growth of host cells and also have antitumor activity. Interferons are classified as a (from leukocytes), (3 (from fibroblasts), and y (from lymphocytes). According to their affinities for the two types of known interferon receptors, interferons IFN-a, IFN-(3, and the less well known IFN-0) and IFN-t are... 

Ribas A, Camacho LH, Lopez-Berestein, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated... 

Intravesical instillation of BCG has been nsed to treat superficial bladder carcinoma and interstitial cystitis. Many reports have confirmed the efficacy of BCG in the treatment of transitional cell bladder cancers and have delineated its adverse effects (SEDA-12, 273) (SEDA-13, 278) (SEDA-15, 344) (SEDA-16, 375) (SEDA-17, 366) (SEDA-18, 328) (SEDA-20, 287) (SEDA-21, 328) (SEDA-22, 336). The exact mechanism of its antitumor activity is unknown, but live BCG provokes an inflammatory response that includes activation of macrophages, a delayed hypersensitivity reaction, and stimulation of T and B lymphocytes and natural killer cells. 

The most famous example of non-specific polysaccharide immunoadjuvants is lentinan isolated from Lentinus edodes. Since 1985, lentinan has been used as an antitumor agent. Lentinan is a (1 3)-/3-glucop)ranan bearing (1 6)-/3-glucopyranoside branches (O Scheme 1). This neutral polysaccharide suppresses the proliferation of sarcoma 180 tumors implanted subcutaneously in mice. Its antitumor activity was due to a host-mediated reaction with participation of thymus or thymus-dependent cells [1]. The lymphokines induced by this polysaccharide enhance the activity of lymphocytes (e. g., macrophages, helper T cells, and/or natural killer cells) in a dramatic manner [2,3,4,5]. Lentinan-like (1 3)-/3-glucopyranan (schizophyllan) contained in the insoluble fraction of Schizophyllum commune has the stracture shown in O Scheme 2 and is known to possess antitumor activity [6]. 

The 6-substituted cyano bipyridine has been generated in 95% yield from bipyridine A-oxide by reaction with trimethylsilylcyanide and dimethylcarbamylchloride.76 This is an improvement on an earlier method that generated 6-cyano bipyridine from the A-oxide in 62% yield using potassium cyanide and benzoyl chloride.77 This ligand has been used in electrochemical studies of rhenium complexes with sterically hindered bipyridine derivatives, as well as a precursor in the synthesis of 6-carbothioamide-bpy, which showed antitumor activity against P-388 lymphocytic leukemia in mice.77... 

Chen W, Huang L (2008) Induction of cytotoxic T-lymphocytes and antitumor activity by a Hposomal Hpopeptide vaccine. Mol Pharm 5 464 71... 

The mechanism by which IFN-a exerts antitumor activity is unclear, particularly in hematological cancers. In melanoma and renal cell carcinoma, antitumor effects may be mediated by augmented immune responses including activation of natural killer lymphocytes and enhanced expression of cell surface antigens (e.g., MHC I and II). However, these mechanisms have not been decisively proved. 

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