Antitumor tumor cell resistance

Research and clinical experience on dmg resistance suggests that tumor cells are particularly adept at genetic selections leading to alterations in the stmcture, function, or synthesis of proteins involved in the antitumor dmg action and detoxification. Multiple mechanisms of resistance have been shown to account for the resistance seen in the clinic (46). 

A compound of a very similar structure is phenazinomycin (67), which has been isolated from mycelial extracts of Streptomyces sp. WK-2057 by Omura et al. [69]. This compound possesses in vivo antitumor activity against experimental murine tumor cells and cytotoxic activity against adriamycin-resistant... 

There is substantial interest in drugs that have little or no antitumor activity when administered alone but that are capable of restoring sensitivity to vinblastine or vincristine in resistant tumor cell populations. 

Graham CH, Kobayashi H, Stankiewicz KS, Man S, Kapitain SJ, Kerbel RS (1994) Rapid acqisition of multicellular drug resistance after a single exposure of mammary tumor cells to antitumor aklylating agents. J Natl Cancer Inst 86 975-982... 

In Vitro Effects Against Acquired Cisplatin-Resistant Tumor Cells. AMD473 was primarily selected for further in vivo antitumor studies (and... 

Stoka, V., Turk, B., Schendel, S.L., Kim, T.-H., Cirman, T., Snipas, SJ., Ellerby, L.M., Bredesen, L., Freeze, H, Abrahamson, M., Bromme, D., Krajewski, S., Reed, J.C., Yin, X.-M., Turk, V., and Salvesen G.S., 2001, Lysosomal Protease Pathways to Apoptosis. Cleavage of Bid, not pro-caspases, is the most likely route../. Biol. Chem. 276 3149-3157 Sun, X. and Ross, D., 1996, Quinone-induced apoptosis in human colon adenocarcinoma cells via DT-diaphorase mediated bioactivation. Chem. Biol. Interact. 100 267-76 Taatjes, DJ. and Koch, T.H., 2001, Nuclear targeting and retention of anthracycline antitumor dmgs in sensitive and resistant tumor cells. Curr. Med Chem. 8 15-29 Tarr, M. and van Helden, PD., 1990, Inhibition of transcription by adriamycin is a... 

Tsuruo T, Oh-hara T, lida H, Tsukagoshi S, Sato Z, Matsuda I, Iwasaki S, Okuda S, Shimizu F, Sasagawa K, Fukami M, Fukuda K, Arakawa M. Rhizoxin, a macrocychc lactone antibiotic, as a new antitumor agent against human and murine tumor cells and their vincristine-resistant sublines. Cancer Res. 1986 46 381-385. 

Heptaplatin (cis-malonate[(4i ,5i )-4,5-bis(aminomethyl)-2-isopropyl-l,3-dioxolane]platinum(II), SKT2053R, Sunpla) has high antitumor activity against various cancer cell lines, including cisplatin-resistant tumor cells. PreUminary results suggested that it is less nephrotoxic than cisplatin. However, a comparative trial showed that intravenous heptaplatin 400 mg/m was more nephrotoxic than intravenous cisplatin 60 mg/m in terms of uremia and proteinuria, which occurred despite the use of hyperosmolar mannitol and appropriate concomitant hydration (fluid intake at least 3500 ml/day) (34,35). 

Drug Delivery - The most widely studied method of reducing toxicity of antitumor agents has continued to be encapsulation in liposomes. The mechanism of drug toxicity reduction and pharmacokinetics of liposome-encapsulated drugs have been reviewed.Methotrexate in lipid vesicles enhanced absorption in tumor cells vitro and resulted in 80% tumor reduction in mice bearing a P1798 lymphosarcoma, a tumor resistant to the same amount of free methotrexate. The unstable nature of aqueous suspensions of CCNU was overcome and the duration of dru action increased, when it was formulated with phosphatidyl choline. Tar-... 

ABSTRACT In mammals, nitric oxide (NO) is a reactive free radical involved in diverse physiological functions. NO and its redox-related forms NO+ and NO react with di(oxygen) and its derivatives, with metalloproteins and thiol-containing proteins. NO-mediated nitrosation of proteins represents an important cellular regulatory mechanism. Biosynthesis of NO is catalysed by nitric oxide synthase (NOS). Three isoenzymes representing distinct gene products have been identified the inducible NOS isoform, the constitutive neuronal and endothelial isoforms. Inducible and constitutive NOSs have the same structural features, but their activities differ in their dependence to calcium and the rate of NO produced. The principal NO-mediated functions in mammals are endothelium-dependent relaxation, neurotransmission and immune response. The role of NO in the antitumor immune response comprises both regulatory and effector functions at the intra- or inter-cellular level. The first function includes inhibition of lymphocyte proliferation or participation in different transduction pathways. The second fiinction includes pro- or anti-tumoral effects and NO-mediated cell toxicity or cell resistance to apoptosis. 

Therefore, the role of NO in the antitumor immune response, comprises both regulatory and effector functions at the intra- or intercellular level. The first functions includes inhibition of lymphocyte proliferation or participation in different transduction pathways. The second functions include pro- or anti-tumoral effects and NO mediated cell toxicity or cell resistance to apoptosis. 

---