Supported by detailed understanding of their mechanism of action, and facilitated by chemical manipulations that have amplified their solubility, the camptothecins have advanced to the forefront of several areas of therapeutic and developmental chemotherapy. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of camptothecin-based multidrug regimens, which are showing important activity in several malignancies. Topotecan and irinotecan are already in widespread use in clinical practice, and newer agents with promising preclinical activity are in various stages of clinical assessment. As knowledge of molecular and biochemical mechanisms of action and resistance continues to expand, newer and better camptothecin-based strategies for treatment of malignant disease are likely to evolve.
The tumor suppressor protein p53 has been implicated in the response of cells to DNA damage. Studies to date have demonstrated a role for p53 in the transcriptional activation of target genes in the cellular response to DNA damage that results in either growth arrest or apoptosis. In contrast, here is demonstrated a role for p53 in regulating the basal level of expression of the cyclin-dependent kinase inhibitor p21 in the absence of treatment with DNA-damaging agents. Wild-type p53-expressing MCF10F cells had detectable levels of p21 mRNA and protein, whereas the p53-negative Saos-2 cells did not. Saos-2 cells were infected with recombinant retrovirus to establish a proliferating pool of cells with a comparable constitutive level of expression of wild-type p53 protein to that seen in untreated MCF10F cells. Restoration of wild-type but not mutant p53 expression recovered a basal level of expression of p21 in these cells. Constitutive expression of luciferase reporter constructs containing the p21 promoter was inhibited by co-transfection with the human MDM2 protein or a dominant-negative p53 protein and was dependent on the presence of p53 response elements in the reporter constructs. Furthermore, p53 in nuclear extracts of untreated cells was capable of binding to DNA in a sequence-specific manner. These results implicate a role for p53 in regulating constitutive levels of expression of p21 and demonstrate that the p53 protein is capable of sequence-specific DNA binding and transcriptional activation in untreated, proliferating cells.
HPV infection results in changes in host gene methylation which, in turn, are thought to contribute to the neoplastic progression of HPV-associated cancers. The objective of this study was to identify joint and disease-specific genome-wide methylation changes in anal and cervical cancer as well as changes in high-grade pre-neoplastic lesions. Formalin-fixed paraffin-embedded (FFPE) anal tissues (n = 143; 99% HPV+) and fresh frozen cervical tissues (n = 28; 100% HPV+) underwent microdissection, DNA extraction, HPV genotyping, bisulfite modification, DNA restoration (FFPE) and analysis by the Illumina HumanMethylation450 Array. Differentially methylated regions (DMR; t test q<0.01, 3 consecutive significant CpG probes and mean Δβ methylation value>0.3) were compared between normal and cancer specimens in partial least squares (PLS) models and then used to classify anal or cervical intraepithelial neoplasia-3 (AIN3/CIN3). In AC, an 84-gene PLS signature (355 significant probes) differentiated normal anal mucosa (NM; n = 9) from AC (n = 121) while a 36-gene PLS signature (173 significant probes) differentiated normal cervical epithelium (n = 10) from CC (n = 9). The CC progression signature was validated using three independent publicly available datasets (n = 424 cases). The AC and CC progression PLS signatures were interchangeable in segregating normal, AIN3/CIN3 and AC and CC and were found to include 17 common overlapping hypermethylated genes. Moreover, these signatures segregated AIN3/CIN3 lesions similarly into cancer-like and normal-like categories. Distinct methylation changes occur across the genome during the progression of AC and CC with overall similar profiles and add to the evidence suggesting that HPV-driven oncogenesis may result in similar non-random methylomic events. Our findings may lead to identification of potential epigenetic drivers of HPV-associated cancers and also, of potential markers to identify higher risk pre-cancerous lesions.
Irinotecan (Campto) is a topoisomerase I inhibitor currently approved for the treatment of metastatic colon cancer. Single-agent irinotecan has also demonstrated modest activity in a number of other advanced solid tumors, including lung, gastric and pancreatic cancer. Preclinical data suggest a potentially additive and/or synergistic interaction between irinotecan and gemcitabine (Gemzar). This combination has demonstrated improved response rates in patients with pancreatic cancer. Unfortunately, a recently reported Phase III trial of gemcitabine with or without irinotecan revealed no survival benefit for the combination. Future combinations of irinotecan continue to be explored in an effort to further improve the treatment of this relatively chemorefractory disease. Thus far, no single agent or combination has been shown to be superior to gemcitabine alone as palliative therapy for advanced/metastatic pancreatic cancer. A promising combination of irinotecan with oxaliplatin (Eloxatin) and fluorouracil will be assessed in a Phase III study.
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