Tumor cell resistance modulators

Two similar types of structures, ortho-alkoxyphenones (12.16) and benzofurans (12.17), were found to lessen multidrug resistance exhibited by tumor cells. Compounds in Hansch analyses normally share the same basic molecular skeleton. In this study of tumor cell resistance modulators, inclusion of an indicator variable allows all the data for both structural types to be pooled into one large data set. The indicator variable, /BF, is given a value of 1 if the compound is a... 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

As described in several monographs [4], bryostatin 1 exhibits significant in vitro and in vivo antineoplastic activity against a range of tumor cell lines including murine leukemia, B-cell lymphoma, reticulum cell sarcoma, ovarian carcinoma, and melanoma. It is also effective in the modulation of apoptotic function [5], the reversal of multidrug resistance [6], and stimulation of the immune system [7]. These unique features displayed by bryostatin 1 are attributed to its high affinity for protein kinase C (PKC) isozymes and its ability to selectively modulate their functions [8]. PKCs are a type of intracellular serine and threonine kinase that... 

Awareness of immunotoxicology was stimulated by a comprehensive review by Vos in 1977, in which he provided evidence that a broad spectrum of xenobiotics alter immune responses in laboratory animals and subsequently may affect the health of exposed individuals. Several additional reviews, as well as national and international scientific meetings, have reinforced these early observations. In several studies, alteration of immune function was accompanied by increased susceptibility to challenge with infectious agents or transplantable tumor cells, indicating the resulting immune dysfunction in altered host resistance. Clinical studies in humans exposed to xenobiotics have confirmed the parallelism with immune dysfunction observed in rodents. The latter sections in this volume describe studies with xenobiotics that resulted in immune modulation in rodents and man. 

TFP (5) was the first phenothiazine demonstrated to modulate MDR in drug-resistant P338 murine leukemia cells. TFP (5) enhanced intracellular accumulation of vincristine and adriamycin (77) in resistant tumor cells by inhibiting outward transport of these anticancer drugs [167]. Studies per-... 

Ecker, G., Chiba, P., Hitzler, M., Schmid, D., Visser, K., Cordes, H. P., et al. Structure-Activity Relationship Studies on Benzofuran Analogs of Propafenone-Type Modulators of Tumor Cell Multidrug Resistance. J. Med. Chem. 1996, 39, 4767-4774. 

Furthermore, the expression and function of the Pgp can be modulated by indirect mechanisms, such as interactions with membrane lipids [67] or inhibition of protein kinase C. The reversal of MDR is established using tumor cells lines that are made resistant by the exposure to an anticancer agent or by transfection of the mdrl or mrpl genes. The parameter most widely used to show the activity of MDR reversal agents is reversal factor (RF). This type of assay assumes that the reversal agent does not show inherent cytotoxicity at the concentrations tested. 

Hosoyama, H. Shigemori, H. Tomida, A. Tsumo, T Kobayashi, J. Modulation of multidmg resistance in tumor cells by taxinine derivatives. Bioorg. Med. Chem. Lett., 1999, 9 389-392. 

Kosugi, K. Saki, J-L Zhang, S. Watanabe, Y Sasaki, H. Suzuki, T Hagiwara, H. Hirata, N. Hirose, K Ando, M. Tomida, A. Tsumo, T. Neutral taxoids from Taxus cuspidata as modulators of multidmg-resistant tumor cells. Phytochem., 2000, 54 839-845. 

Ecker G, Chiba P, Hitzler M, Schmid D, Visser K, Cordes HP, Csollei J, Seydel JK, Schaper KJ. Structure-activity relationship studies on benzofurane analogs of propafenone-type modulators of tumor cell multidrug resistance. J Med Chem 1996 39 4767-74. 

Bowen, W.D., Jin, B., Blann, E., Vilner, B.J., Lyn-Cook, B.D., 1997. Sigma receptor ligands modulate expression of the multidrug resistance gene in human and rodent brain tumor cell lines. Proceedings of the American Association for Cancer Research 38 (3206), 479. 

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