Modulation of drug and radiation resistant genes

Details Modulation of drug and radiation resistant genes Modulation of drug and radiation resistant genes

1997-05-23

1999-11-23

LeGuyader, John L.

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

435 6, 435 9131, 4353201, 435366, 435375, 536 231, 536 232, 536 2431, 536 245, C12N 1585, C07H 2104, C12Q 168

Patent

active

059899085

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to the modulation of the drug resistant phenotype in mammalian, including human, cancer cells, which will make cancer cells sensitive to chemotherapy treatment and/or radiation treatment.


BACKGROUND OF THE INVENTION

Despite tremendous strides in understanding the molecular basis of cancer (1),.sup.1 treatment of human cancer is still limited by the toxicity of chemotherapeutic agents and the development of intrinsic or acquired resistance to these drugs. Cis-diamminedichloroplatinum (II) (cisplatin) is one of the most widely-used anticancer agents, active in the treatment of ovarian, testicular, head-and-neck, non-small cell lung and brain tumors, among others (2). However, the rapid development of resistance to cisplatin represents an important challenge to clinicians and laboratory investigators alike. Therefore, understanding the biochemical and molecular basis of cisplatin resistance may potentially result in the development of rational approaches to circumvent this problem. At the core of understanding cisplatin resistance lies the realization of both the similarities and differences between the mechanisms of cisplatin action and resistance and that of other chemotherapeutic agents. Cisplatin-resistant cells display a unique cross-resistance pattern to multiple agents, including anti-metabolites such as 5'-fluorouracil and methotrexate, DNA polymerase inhibitors such as azidothymidine (AZT), and topoisomerase inhibitors such as camptothecin and etoposide. This "atypical" multidrug resistance is both phenotypically and molecularly distinct from the "classical" multidrug resistance which may involve overexpression of the MDR-1 gene (3).
A cursory review of the literature in cisplatin resistance quickly points to a potentially confusing array of mechanisms purported to be involved in this process, most of them seemingly disparate and unrelated. Recent advances in the workings of signal transduction in normal and cancer cells have led to a more cohesive picture of cellular pathways involved in the response to extracellular agents (e.g., growth factors, tumor promoters, viruses, and chemotherapeutic agents). This in turn has merged seemingly independent biochemical processes activated in response to various stimuli. An important molecular mechanism in cisplatin resistance concerns the c-fos proto-oncogene. The Fos protein dimerizes with the c-jun gene product to drive many important cell processes by transcriptional activation of AP-1-responsive genes (4). Numerous AP-1-responsive genes have been identified which participate in DNA synthesis and repair processes and which have been implicated in cisplatin resistance (5). These include metallothionein, DNA polymerase .beta., thymidylate synthase, topoisomerase II, and glutathione-S-transferase. Furthermore, the Fos/Jun heterodimers are thought to mediate the effects of H-ras activation following growth factor activation (6). And protein kinase C is a known participant in cellular signalling pathways leading to the activation of c-fos gene expression (4).


SUMMARY OF THE INVENTION

This invention elucidates signal transduction processes which mediate cellular response to extracellular agents. Common signalling pathways, e.g., those involving c-fos/c-jun become activated in response to diverse stimuli such as growth factors and chemotherapeutic agents. See FIGS. 2 and 3. The activation of the Fos/Jun complex in the nucleus, which typically occurs in a transient fashion, is a key feature of this response. These transient increases in gene expression then result (through transcriptional activation of AP-1responsive genes) in long term phenotypic changes. However, there is also specificity within the system. Therefore, Fos/Jun activation by cisplatin may lead to induction of genes involved in DNA synthesis and repair, metallothionein, and glutathione-S-transferase, whereas its activation by actinomycin D or etoposide, compounds known to be in the classical multidrug-resistant phenotype, may lead to induction of the mdr

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