Gene directed enzyme prodrug therapy for cancer

One strategy for gene therapy in malignant disease is gene directed enzyme prodrug therapy (GDEPT). An exogenous enzyme gene is delivered to tumour cells. The enzyme, when expressed, can convert a non-toxic prodrug into a cytotoxic species that is capable of killing the cell in which it has been produced. The most frequently used systems are HSV thymidine kinase with ganciclovir and E. coli cytosine deaminase with 5-fluorocytosine. The bystander effect is of key importance to GDEPT: This describes the local spread of active species from cells that express the enzyme to kill adjacent, untransduced cells. The ultimate success of GDEPT will depend on the ability to achieve efficient gene delivery to and expression in target cells, whilst minimising expression in other tissues. A variety of techniques exist to achieve this goal, including loco-regional administration, manipulation of tumour blood supply and use of tumour-specific promoters to drive enzyme gene expression.     

"Stockless" cost reduction in the operating room

St. Paul-Ramsey Medical Center in St. Paul, MN became one of the first hospitals in the United States to initiate a "stockless" par level inventory system. Successes with stockless led the hospital to look at implementing it in the OR to achieve a reduction of expense to revenue. Materiel Management and Surgical Services discussed a number of issues relevant to implementing a stockless program, including product flow, accuracy and cost of case carts and preference cards, item pricing, committed usage of items brought into the system and establishment of a steering committee. Specific OR issues and practices required evaluation and adjustment, such as the routine use of emergency direct ordering. Information systems support was brought in and a products committee established to do education and oversee the program. Savings for 1993-94 were $185,146.     

Effects of two stressors on behaviour in the elevated X-maze: preliminary investigation of their interaction with 8-OH-DPAT

Effects of water deprivation and restraint were compared in the rat elevated X-maze. Water deprivation for 12–48 h increased corticosterone and had a duration-dependent anxiolytic effect in the elevated X-maze, increasing the ratio of open/total arm entries (OTR) and the proportion of time spent on the open arms (% time) without affecting total entries. Brain 5HIAA/5HT was increased only after 24 or 48 h deprivation. Restraint for 15 min also increased plasma corticosterone and brain 5HIAA/5HT but had no effect on behaviour in the elevated X-maze when rats were tested immediately afterwards. However, 1 h restraint was anxiogenic in the elevated X-maze immediately after release, reducing OTR and % time, but with a less consistent reduction in total entries; reductions in OTR and % time were still present 24 h later. The 5HT_1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.1–0.2 mg/kg), administered 10 min before testing in the elevated X-maze, had anxiogenic actions in non-stressed rats. The effect of 0.1 mg/kg 8-OH-DPAT was not significantly altered by 24 or 48 h water deprivation but was abolished by restraint for 1 h immediately beforehand, despite the anxiogenic effect of restraint alone. Similar mutual antagonism of 8-OH-DPAT and restraint occurred when the dose of 8-OH-DPAT was increased to 0.2 mg/kg. Twenty-four hours after restraint, restrained rats which had received 8-OH-DPAT (0.1–0.2 mg/kg) still did not show any significant anxiogenic effect compared with non-restrained vehicle treated controls. Restraint-induced deficits in elevated X-maze exploration may prove a useful model with which to study the pharmacology of depression-related anxiety. However, the effects of the stressors examined, and their interaction with 8-OH-DPAT in the elevated X-maze, appear to depend on the nature of the stressor.     

Destruction of WiDr multicellular tumor spheroids with the novel thymidylate synthase inhibitor 1843U89 at physiological thymidine concentrations

The activity of a novel thymidylate synthase inhibitor, 1843U89, against WiDr human colon carcinoma multicellular tumor spheroids was investigated. Continuous exposure of the spheroids to 3 nM 1843U89 for 10 days resulted in spheroid disruption, whereas 100 nM methotrexate (MTX) was required for similar effects. Short-term treatment experiments demonstrated that a 3-day exposure to 100 nM 1843U89 caused spheroid disruption 9 days after drug removal. A 4-day exposure to 10 nM 1843U89 caused spheroid disruption 8 days after drug removal. In contrast, treatment with 10 or 100 nM 1843U89 for 6–48 h or treatment with 1 nM 1843U89 for up to 5 days caused only growth delay. Continuous exposure of spheroids to 30 nM 1843U89 in the presence of 0.05–0.3 M thymidine was as effective in causing spheroid disruption as treatment in the absence of thymidine, but treatment in the presence of 0.7–3.0 M thymidine caused partial reversal of spheroid disruption. The results of these experiments suggest that 1843U89 should have potent solid tumor activity in humans but should be less effective in mice due to differences in circulating thymidine levels (0.1 vs 1 M, respectively).     

The failing Fontan with atrial flutter: a successful surgical option

Two successful cases of eliminated atrial flutter and improved clinical status for Fontan patients are presented. An operation combining introduction of an extracardiac conduit for the Fontan connection, to direct all systemic venous blood away from the atrium, and atrial pathway division and cryoablation, is a useful surgical option for failing Fontan patients.