This novel approach to the treatment of adenocarcinoma of the stomach is feasible. The neoadjuvant systemic therapy results in significant primary tumor regression. The determination of whether systemic or IP components of the program contribute to decreased recurrence or increased survival awaits a prospectively randomized clinical trial.

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A bystander effect is described when nontransduced or genetically unmodified cells are killed during death of genetically modified tumor cells transduced with a suicide gene. The "bystander effect" greatly enhances the efficacy of the herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy approach for cancer. The mechanism of the bystander effect is controversial. In this study, we examined the role of intercellular gap junction communication (GJIC) for the bystander effect in human gastrointestinal tumor cells. Our results show that the extent of the bystander effect varied amongst the tumor cell lines; pancreatic cancer cells BXPC-3 exhibited excellent bystander effects in vitro and in vivo studies whereas other gastrointestinal tumor cell lines such as pancreatic cancer cells MIAPACA-2, and colon cancer cells HT-29 showed poor bystander effects. Bystander effects were only found in the presence of cell-to-cell contact. The extent of the bystander effect was independent of the level of HSV-TK activity in the transduced tumor cells and was correlated with GJIC as demonstrated by an in vitro dye-transfer assay. Expression of the mRNA levels of gap junction protein connexin 43 was 8- to 26-fold or greater and connexin 26 gene expression was 2- to 229-fold greater in BXPC-3 cells compared to HT-29, MIAPACA-2, and PANC3 cells. Our results suggest that intercellular communication is essential for the bystander effect. The correlation between GJIC and the extent of the bystander effect suggest a role for GJIC in mediating the bystander effect. Analysis of tumors for GJIC or expression of gap junction proteins may identify the subset of patients suitable for gene therapy with the HSV-TK/GCV approach.

Techniques have been developed to measure FdUMP, the active metabolite of 5-FUra; thymidylate synthetase (TMP synthase; 5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45), the target enzyme for this antimetabolite; and dUMP, the substrate that competes with FdUMP for binding to TMP synthetase. As The methods described are sufficiently sensitive to allow these biochemical parameters of 5-FUra action to be measured in cell culture or in needle biopsy samples of human tumors.5-Fluorouracil is widely used either as a single agent or in combination with other drugs in the treatment of carcinomas of the breast, ovary, and gastrointestinal tract (1). Such chemotherapy will induce objective responses in approximately 30% of patients with disseminated breast cancer, and the survival time of responding patients is more than doubled by this drug (2). Although 5-FUra will produce objective responses in about 20% of patients with gastrointestinal cancer, the effect of this drug on patient survival remains unclear (3, 4). However, the majority of patients with these diseases do not experience prolongation of life due to 5-FUra therapy; yet they undergo toxicity and, in addition, cannot be treated with alternate drug therapies until failure on treatment protocols involving 5-FUra is confirmed. Hence, it would be invaluable to the improved clinical use of this drug if the tumors that would ultimately respond to 5-FUra could be distinguished from nonresponding neoplasms at an early stage in chemotherapy on the basis of some biochemical parameter or set of parameters of critical importance to successful chemotherapy with this agent. Such a test would be most useful if it were sensitive enough to be performed with specimens from needle biopsies of tumors.The chemotherapeutic effects of 5-FUra are thought to be primarily due to inhibition of thymidylate synthetase (TMP synthase; 5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45)'by its 2'-deoxy-5'-monophosphate (FdUMP) (1). FdUMP has been shown to form a covalent complex with TMP synthetase in the presence of 5,10-methylenetetrahydrofolate (5,10-CH2-H4PteGlu), the folate cofactor for the synthesis of thymidylate (5, 6). The ability of FdUMP to form this titrating complex has been shown to be decreased in the presence of dUMP (7), the cellular pools of which expanded significantly after 5-FUra treatment in P1534 mouse leukemia (8) and in mouse colon tumors 38 and 51 in vivo (9). Accumulation of the dUMP pool was not as extensive in the L1210 or W256 tumors (10). We now report the development and initial application of ultrasensitive techniques for the measurement of FdUMP, TMP synthetase, and dUMP in sufficiently small quantities of tissue to allow assay of these variables in small tumor biopsies. MATERIALS AND METHODSMethotrexate-resistant Lactobacillus casei (L. casei/MTX) (11) cells were grown in a 2000-liter fermenter in minimal media (12). Sonicates of these cells were treated with RNase, DNase, and (NH4)2SO4 (12); then they were ...

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