Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-10-25
2003-02-18
Benzion, Gary (Department: 1656)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
Reexamination Certificate
active
06521407
ABSTRACT:
The present application concerns methods of selecting the most appropriate therapy for patients suffering from cancer. The application is particularly concerned with measuring the resistance of cancer cells to anti-cancer agents.
Although radiotherapy and chemotherapy have been responsible for curing many people of cancer in the latter half of this century, there still remain a large number of tumours which either show little response to treatment, or respond initially only to recur later. In particular, women treated for ovarian cancer with platinating agents often show encouraging initial responses to chemotherapy (which often involves the use of cis-diamminedichloroplatinum (CDDP) as the drug of first choice), but by 5 years after diagnosis, ⅔ of them have succumbed to their disease. Similarly lung cancer patients may respond favourably to combination chemotherapy regimens containing CDDP at the outset of treatment but very few experience long term survival. A better understanding of the mechanisms underlying the responsiveness of cancers to CDDP could help predict which patients are most likely to benefit from CDDP or whether alternative cytotoxic agents such as taxol or different therapies such as radiotherapy might be appropriate. Understanding treatment response mechanisms also holds the possibility of selectively modulating these mechanisms to improve the treatment of human cancer using, for example, CDDP.
It has become increasingly apparent that certain oncogenes and tumour suppressor genes may not only be implicated in carcinogenesis, but can also influence the sensitivity of malignant cells to therapeutic agents. Attempts have therefore been made to use these and other genes to try and predict the therapeutic response of human cancer to the presently available treatment modalities such as radiotherapy and/or cytotoxic chemotherapy. Research up to the present time, however, has generally attempted to only examine the expression of single tumour related genes as methods of predicting therapeutic response. Research in the public domain has suggested that mutations in the p53 tumour suppressor gene, which can be found in around 50% of common cancers such as those of the breast, lung and ovary, are associated with resistance to treatment with cytotoxic drugs or radiation. Despite a considerable body of work, however, there are at present no successful clinical tests by which the detection of mutations in the p53 gene alone can be used to predict with an acceptable degree of certainty whether or not a patients cancer is likely to respond to chemotherapy with, for example, platinating agents or the newer cytotoxic agents such as taxanes (e.g. Paclitaxel (TAXOL)).
The effect of the expression of single genes alone on the response of human cancer cell lines to treatment with cytotoxic drugs such as CDDP (cisdiamminedichloroplatinum) has been studied in human in vitro cell lines because these present a model system relevant to the response of human cancer in the clinic. In particular, they exhibit the range of sensitivities to cytotoxic drugs and ionising radiation usually encountered in the clinic. Discoveries in human in vitro cell lines, therefore, have a strong possibility of being able to be translated into clinically useful tests for how well cancers may be expected to respond to treatment.
The progress of cells through the cell cycle is governed by holoenzymes formed by a combination of proteins called cyclins, whose levels fluctuate throughout the cell cycle, and cyclin dependent kinases (CDKs) which become active when they join with cyclins. The cyclin/CDK complexes can be. inhibited by proteins termed cyclin dependent kinase inhibitors (CDKIs) which include the protein p21 WAF1/CIP1 (p21).
The protein products of the cyclin D1 and B1 genes and their respective cyclin-dependent kinase partners CDK4 and CDK1 have been studied. Cyclin D1 and CDK4 control the progress of cells through the cell cycle checkpoint between G1 and S-phase (the phase of DNA synthesis). Cyclin B1 and CDK1 control the cell cycle checkpoint just before mitosis. The expression of cyclin D1 protein in a series of 16 human cancer cell lines has been shown to be related to their intrinsic resistance to the cytotoxic drug CDDP (Warenius et al., 1996). Cyclin D1 protein levels, however, showed no relationship with radiosensitivity, another treatment modality. The relationship between cyclin D1 and CDDP resistance is not, however, strong enough on its own to provide the basis of clinically useful predictive assays.
Paclitaxel, which is a member of the class of anti-cancer drugs known as taxanes, has been shown clinically to be of benefit when added to treatment with platinating agents in the clinical treatment of ovarian cancer. It has been reported that cells can become more sensitive to Paclitaxel when they lose normal p53 function as a result of infection with human papilloma virus constructs or SV40 virus constructs (Wahl et al, Nature Medicine, vol. 2, No. 1, 72-79, 1996). This is thought to result from increasing G2/M arrest and apoptosis. However, it is not the case that all p53 mutant cancer cells are sensitive to Paclitaxel (TAXOL). Accordingly, based on this correlation on its own these studies have not been able to engender a reliable predictive method for determining a likely effective treatment in specific cases.
Thus, there are no indicators that measuring the mutational status or levels of expression of the protein products of single oncogenes, proto-oncogenes or tumour suppressor genes in human cancer cells would be able to provide the basis of a reliable clinical test for whether clinical tumours were likely to respond to treatment with chemotherapeutic agents, including platinating agents and CDDP.
Although radiotherapy has been responsible for curing many people of cancer in the latter half of this century, there still remain a large number of tumours which either show little response to treatment, or respond initially only to recur later. A better understanding of the mechanisms underlying the responsiveness of cancers to radiotherapy could help predict which patients are most likely to benefit from radiotherapy, and also holds the possibility of selectively modulating these mechanisms to improve the treatment of human cancer using radiotherapy.
The molecular basis of intrinsic radiosensitivity has been under investigation for many years. A considerable body of research has focused on the degree of DNA damage and its subsequent repair as reflected in the incidence of double strand breaks (dsbs) in the DNA (Kelland et al, 1988; Schwartz et al, 1991), the residual damage remaining in the DNA after cellular rejoining of dsbs (Nunez et al, 1995; Whitaker et al, 1995), and the fidelity of DNA repair (Powell & McMillan, 1994). In addition to DNA damage, however, it has become increasingly apparent that certain oncogenes and tumour suppressor genes may not only be implicated in carcinogenesis, but can also influence the sensitivity of malignant cells to ionising radiation.
As a result of this growing evidence of the role of oncogenes and tumour suppressor genes in the sensitivity of malignant cells to therapeutic agents, attempts have been made to use these and other genes to try and predict the therapeutic response of human cancer to the presently available treatment modalities such as radiotherapy and/or cytotoxic chemotherapy. Research up to the present time, however, has generally attempted to only examine the expression of single tumour related genes as methods of predicting therapeutic response. When investigating the relationship between expression of a chosen gene and intrinsic radiosensitivity, consideration has not necessarily been given as to whether other candidate genes than the one selected for study might also have an affect on the outcome of experiments.
Research into the role of individual genes has focused on a number of cell cycle genes and signal transduction genes. Transfection of normal cell lines with dominant oncogenes such as myc and ras (McKenna et al, 1991
Seabra Laurence Anthony
Warenius Hilmar Meek
Benzion Gary
Rothwell Figg Ernst & Manbeck P.C.
Strzelecka Teresa
TheRyte Limited
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