Oligonucleotides as modulators of cancer gene expression.

The delineation of gene function has always been an intensive subject of investigations. Recent advances in the synthesis and chemistry of oligonucleotides have now made these molecules important tools to study and identify gene function and regulation. Modulation of gene expression using oligonucleotides has been targeted at different levels of the cellular machinery. Triplex forming oligonucleotides, as well as peptide nucleic acids, have been used to inhibit gene expression at the level of transcription; after binding of these specific oligonucleotides, conformational change of the DNA's helical structure prevents any further DNA/protein interactions necessary for efficient transcription. Gene regulation can also be achieved by targeting the translation of mRNAs. Antisense oligonucleotides have been used to down-regulate mRNA expression by annealing to specific and determined region of an mRNA, thus inhibiting its translation by the cellular machinery. The exact mechanism of this type of inhibition is still under intense investigation and is thought to be related to the activation of RNase H, a ribonuclease that is widely available that can cleave the RNA/DNA duplex, thus making it inactive. Another well-characterized means of interfering with the translation of mRNAs is the use of ribozymes. Ribozymes are small catalytic RNAs that possess both site specificity and cleavage capability for an mRNA substrate, inhibiting any further protein formation. This review describes how these different oligonucleotides can be used to define gene function and discusses in detail their chemical structure, mechanism of action, advantages and disadvantages, and their applications.

Primary lymphoepithelioma-like carcinoma of the lung in a child. Report of an Epstein-Barr virus-related neoplasm.

Lymphoepithelioma-like carcinoma (LEC), an undifferentiated carcinoma with pronounced lymphocytic infiltration, often is seen in the nasopharynx as well as in other areas. But such primary pulmonary lung neoplasms in children are rare, and we present the first reported case of primary pulmonary LEC in a child.

Increased specific binding of insulin-like growth factor-I in healing cutaneous wounds.

Insulin-like growth factor-I is a polypeptide hormone structurally related to insulin. It is a potent mitogen that promotes growth and differentiation in many tissues. A role for insulin-like growth factor-I in wound healing is suggested by its rapid rise in levels and increased insulin-like growth factor-I messenger RNA expression in tissue after wounding. We designed our study to characterize possible changes in insulin-like growth factor-I receptor binding during wound healing. Surgical wounds created on the abdominal skin of anesthetized New Zealand White rabbits were either left open or closed primarily. Size- and weight-matched specimens were harvested at wounding time (day 0), and at 1, 4, 7, 38, and 50 days after wounding. Preliminary experiments showed that the greatest difference in specific binding occurred between day 0 and day 7. (125)I-insulin-like growth factor-I binding studies were performed on frozen tissue specimens and autoradiography was performed and analyzed by computerized densitometry. Scatchard analysis of the binding data showed a single class of insulin-like growth factor-I binding sites whose affinity that is, binding constant (K(d) = 0.6 x 10(-9)) did not change significantly over time; in contrast there was a threefold increase in the number of receptors per milligram tissue in day 7 wound tissue versus normal skin harvested at day 0 (17.3 +/- 2.6 x 10(10) versus 4.7 +/- 2.5 x 10(10), respectively, p < 0.05). Binding inhibition experiments showed that (125)I-insulin-like growth factor-I binding was most specific to insulin-like growth factor-I with insulin-like growth factor-I > insulin-like growth factor-II > insulin. This increase in binding was due to upregulation of insulin-like growth factor-I receptors rather than increased levels of insulin-like growth factor-I binding protein as less than 20% of the threefold increase in binding at day 7 could be attributed to insulin-like growth factor-I binding protein in membrane-free extracts. The presence of specific, high-affinity insulin-like growth factor-I receptors in the skin and their upregulation at day 7 after wounding suggest that insulin-like growth factor-I plays an important role during wound healing.

Local recurrence in breast cancer: implications for systemic disease.

BACKGROUND: Recurrence in breast carcinoma follows a pattern of growth marked by local, regional, or widespread dissemination. Local recurrence may be the harbinger of systemic disease or failure of local control. Delineation of these processes may have implications in treatment. METHODS: A retrospective review found 1,171 patients with stages I and II breast cancer from 1978 to 1990 treated at the City of Hope Medical Center. RESULTS: Twenty-seven percent (n = 313) of patients developed recurrences. These were classified as local, including chest wall and regional nodes (n = 40), local and distant (n = 63), and distant (n = 210). Mean follow-up was 60 months. Multivariate analysis demonstrates tumor size was not different between the three groups, but the presence of positive lymph nodes was: local = 51%, local and distant = 78%, and distant = 64%. The disease-free interval was longest in the local group (42 months) versus the local and distant group (23 months) and distant group (39 months). Median survival was calculated from the time of recurrence: local = 90 months, local and distant = 26 months, and distant = 16 months. CONCLUSIONS: A group of patients with local recurrence have improved survival and do not develop distant disease. This group may benefit from aggressive surgical treatment to control local disease. These data suggest that a subset of breast tumors can act locally aggressive without metastatic potential.

Beyond palliative mastectomy in inflammatory breast cancer--a reassessment of margin status.

BACKGROUND: Inflammatory breast cancer is a locally advanced tumor with an aggressive local and systemic course. Treatment of this disease has been evolving over the last several decades. The aim of this study was to assess whether current therapies, both surgical and chemotherapeutic, are providing better local control (LC) and overall survival (OS). We also attempted to identify clinical and pathologic factors that may be associated with improved OS, disease-free survival (DFS), and LC. METHODS: A 25-year retrospective review performed at the City of Hope National Medical Center identified 90 patients with the diagnosis of inflammatory breast cancer. RESULTS: Of the 90 patients identified with inflammatory breast cancer, 33 received neoadjuvant therapy (NEO) consisting of chemotherapy followed by surgery with radiation (n = 26) and without radiation (n = 7). Fifty-seven patients received other therapies (nonNEO). Treatments received by the nonNEO group consisted of chemotherapy, radiation, mastectomy, adrenalectomy, and oophorectomy, alone or in combination. The median follow-up was 28.9 months for the NEO group and 17.6 months for the nonNEO group. Borderline significant differences in the OS distributions between the two groups were found (P = .10), with 3- and 5-year OS for the NEO group of 40.0% and 29.9% and for the nonNEO group of 24.7% and 16.5%, respectively. DFS and LC were comparable in the two groups. Lower stage was associated with an improved OS (P < .05). The 5-year OS for stage IIIB was 30.9%, compared to 7.8% for stage IV. In those patients with stage III disease who were treated with mastectomy and rendered free of disease, margin status was identified by univariate analysis to be a prognostic indicator for OS (P < .05). The 3-year OS, DFS, and LC for patients with negative margins were 47.4%, 37.5%, and 60.3%, respectively, compared to 0%, 16.7%, and 31.3% in patients with positive margins. CONCLUSIONS: This study suggests that in patients with inflammatory breast cancer and nonmetastatic disease, an aggressive surgical approach may be justified with the goal of a negative surgical margin. Achievement of this local control is associated with a better overall outcome for this subset of patients. The ability to obtain negative margins may further identify a group of patients with a less aggressive tumor biology that may be more responsive to other modalities of therapy.