Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines

BACKGROUND: Topotecan (TPT) is a topoisomerase I poison that exhibits antineoplastic activity. Analysis of the cytotoxic effects of combinations of TPT and other anticancer agents has been limited. PURPOSE: We assessed the cytotoxic effects produced by combinations of TPT and other antineoplastic agents in experiments involving multiple human cancer cell lines of diverse histologic origins. METHODS: The cytotoxic effects of various antimetabolites (fluorouracil, methotrexate, or cytarabine), antimicrotubule agents (vincristine or paclitaxel [Taxol]), DNA alkylating agents (melphalan, bis[chloroethyl]nitrosourea [BCNU], or 4-hydroperoxycyclophosphamide [4HC]), and a DNA-platinating agent (cisplatin), alone and in combination with TPT, were measured in clonogenic (i.e., colony-forming) assays. HCT8 ileocecal adenocarcinoma, A549 non-small-cell lung carcinoma, NCI-H82ras(H) lung cancer, T98G glioblastoma, and MCF-7 breast cancer cell lines were used in these assays. The data were analyzed by the median effect method, primarily under the assumption that drug mechanisms of action were mutually nonexclusive (i.e., completely independent of one another). For each level of cytotoxicity (ranging from 5% to 95%), a drug combination index (CI) was calculated. A CI less than 1 indicated synergy (i.e., the effect of the combination was greater than that expected from the additive effects of the component agents), a CI equal to 1 indicated additivity, and a CI greater than 1 indicated antagonism (the effect of the combination was less than that expected from the additive effects of the component agents). RESULTS: When the mechanisms of drug action were assumed to be mutually nonexclusive, virtually all CIs for combinations of TPT and either antimetabolites or antimicrotubule agents revealed cytotoxic effects that were less than additive. The CIs calculated at low-to-intermediate levels of cytotoxicity for combinations of TPT and the DNA alkylating agents melphalan, BCNU, and 4HC also showed drug effects that were less than additive; in most cases, however, nearly additive or even synergistic effects were observed with these same drug combinations at high levels of cytotoxicity (i.e., at > or = 90% inhibition of colony formation). Results obtained with combinations of TPT and cisplatin varied according to the cell line examined. With A549 cells, less than additive effects were seen at low-to-intermediate levels of cytotoxicity, and more than additive effects were seen at high levels of cytotoxicity. With NCI-H82ras(H) cells, synergy was observed over most of the cytotoxicity range. CONCLUSIONS AND IMPLICATIONS: TPT cytotoxicity appears to be enhanced more by combination with certain DNA-damaging agents than by combination with antimetabolites or antimicrotubule agents. Interactions between TPT and other drugs can vary depending on the cell type examined. Further investigation is required to determine the basis of the observed effects and to determine whether these in vitro findings are predictive of results obtained in vivo.     

Men, medicine and machines

PURPOSE: To examine the management and possible causes of primary valve malfunction of the Krupin eye valve with disk. METHODS: The authors reviewed the results of 113 patients undergoing implantation of the Krupin eye valve with disk and identified eight patients with primary valve malfunction requiring surgical revision. RESULTS: Valve revision involved manipulation (n = 1 case), explantation of the malfunctioning valve and implantation of a new valve (n = 2), and amputation of the valve (n = 5). Six of eight patients had final intraocular pressures of < 21 mmHg on one or no medications at a mean interval of 15.9 months (range 5-36) after surgical revision. Transient postoperative hypotony was noted in three patients and chronic hypotony with loss of light perception in one patient. One explanted valve was examined and found to have partially fused leaflets. CONCLUSIONS: Surgical revision in cases of primary valve malfunction of the Krupin eye valve with disk may be accomplished relatively safely with an acceptable level of postoperative complications. The etiology of primary valve malfunction may be related to the sterilization process and prolonged storage before implantation.     

Contractor Prebid Planning Principles

Planning is an essential function of project management. Yet, many small- and medium-sized contractors do a relatively poor job of operational planning. Better prebid plans will reduce costs, shorten schedules, and improve labor productivity. Unfortunately, the published literature offers little guidance for smaller contractors on what constitutes effective planning. Most papers describe planning as a macrolevel process for owners. Most emphasize scope definition for industrial projects. This paper describes a microlevel planning process for contractors. It consists of eight steps which are: (1) assess contract risks; (2) develop a preliminary execution plan; (3) develop site layout plans; (4) identify the sequences that are essential-to-success; (5) develop detailed operational plans; (6) develop proactive strategies to assure construction input into design; (7) revise the preliminary plan; and (8) communicate and enforce the plan. The entire process is illustrated with a case study project and is fully illustrated with figures which show how to integrate the work of multiple contractors, keep key resources (crews or equipment) fully engaged with no downtime, provide time buffers so the work of follow on crews can be efficiently done, expedite the schedule using multiple work stations and concurrent work, ways to communicate the work plan to the superintendent and foremen, and how to assess the feasibility of various work methods. The steps are easy to understand and implement. They will yield immediate positive results.     

An extended panel of hamster-human hybrids for chromosome 2q

A hamster-human hybrid containing only the q arm of chromosome 2 has been used to construct a panel of hybrids bearing reduced regions of chromosome 2 using the technique of irradiation fusion gene transfer. The human chromosome 2 carried the Ecogpt gene and all hybrids were selected using this marker. The integrated Ecogpt gene was localized to the region 2q33-34, resulting in the selective retention of this region in the hybrids. These data were combined with another previously constructed panel of hybrids containing regions of 2q, which were enriched for the region 2q36-37. The combined hybrid panel is useful for the mapping of new markers to defined regions of chromosome 2 and for the cloning of genes located on 2q by a positional strategy.     

Denial of illness in stroke

BACKGROUND: The effects of stroke on classically nondominant hemisphere functions have received less attention than those on the dominant hemisphere, but visuospatial neglect and denial of illness both produce significant morbidity. SUMMARY OF COMMENT: The early literature on denial of illness is discussed and the etiological theories are examined. These are explanations based on deficits of higher mental function, impaired sensory input (especially proprioceptive), an abnormal representation of body image, psychodynamic defense mechanisms, and/or premorbid personality factors. CONCLUSIONS: Denial of illness is an important consequence of stroke. No explanation thus far proposed is entirely satisfactory. The consequences on rehabilitation and strategies for therapy have not been adequately investigated.     

Fetus-in-fetu with malignant recurrence

Fetus-in-fetu is an unusual condition in which a vertebrate fetus is enclosed within the abdomen of another fetus. These occurrences are usually benign. This report describes an instance of malignant recurrence after resection of a fetus-in-fetu.     

RNA movement between the nucleus and the cytoplasm

The past year has seen significant advances in our understanding of the mechanism of RNA movement between the nucleus and the cytoplasm. The emerging view is that proteins bind to and escort RNAs to their proper subcellular location. The discovery of peptide signals that target nuclear export and the identification of novel protein mediators of RNA export are examples of significant recent discoveries.