The human transmembrane molecule LAR is a protein tyrosine phosphatase (PTPase) with a cell adhesion molecule‐like extracellular receptor region. The structure of LAR hinted at its involvement in the regulation of tyrosine phosphorylation through cell‐cell or cell‐matrix interactions. We show here that LAR is expressed on the cell surface as a complex of two non‐covalently associated subunits derived from a proprotein. The LAR E‐subunit contains the cell adhesion molecule‐like receptor region, while the LAR P‐subunit contains a short segment of the extracellular region, the transmembrane peptide and the cytoplasmic PTPase domains. Proprotein processing occurs intracellularly. Analysis of LAR mutants suggested that cleavage occurs in the LAR extracellular region at a paired basic amino acid site by a subtilisin‐like endoprotease. A single amino acid substitution at this site blocked LAR proprotein cleavage. The LAR E‐subunit is shed during cell growth, suggesting that LAR receptor shedding may be a mechanism for regulating PTPase function. The use of immunohistochemistry techniques on human tissues demonstrated the expression of LAR by various cell lineages, including epithelial cells, smooth muscle cells and cardiac myocytes. The LAR gene is mapped to chromosome 1, region p32–33, which contains candidate tumor suppressor genes.

The maytansinoid drug DM1 is 100-to 1000- Colorectal cancer is one of the most common malignancies and is among the leading causes of death from cancer. Surgical resection is the primary treatment modality for these tumors, but about half of all patients will die of disseminated disease (1). Because of the high incidence and poor prognosis of patients with metastatic disease, successful treatment of colorectal cancer requires effective systemic therapy in addition to surgery, either as adjuvant treatment to surgery or for primary treatment of those 25% of all patients for whom surgery alone cannot achieve a complete response (2). Unfortunately, the conventional systemic treatment options for colon cancer, including radiation therapy, chemotherapy, and immunotherapy, have limited efficacy (3, 4). To date, 5-fluorouracil (5-FU) has served as the standard cytostatic drug for adjuvant therapy after surgery. However, the overall response rate to 5-FU is less than 25%, and the treatment has not significantly improved patient survival (1-3). Although the improved regimen of 5-FU plus levamisole in the adjuvant setting has proven to be more effective in patients with stage II and III colorectal cancers, the estimated reduction in the mortality rate is still less than 30% (2, 5). Thus, there is an urgent clinical need for new agents with greater efficacy.Conventional chemotherapeutic agents are limited in their therapeutic effectiveness by severe side effects due to their poor selectivity for tumors. The development of monoclonal antibodies against specific tumor antigens made it possible to think of enhancing the selectivity of anticancer drugs by a targeted delivery approach. However, several such reported attempts using monoclonal antibodies and the anticancer drugs doxorubicin (6), methotrexate (7), and Vinca alkaloids (8), have been largely unsuccessful. These antibody-drug conjugates were only moderately potent and usually less cytotoxic than the corresponding unconjugated drugs. In fact, antigenspecific cytotoxicity toward cultured tumor cells was rarely demonstrated (6-8). In vivo therapeutic effects with these conjugates in tumor xenograft animal models were, in general, observed only when the treatments were commenced before the tumors were well established (8) or when exceedingly large doses (up to 90 mg/kg, drug equivalent dose) were used (6). It is, therefore, not surprising that in human clinical trials, no significant antitumor effects were observed with these agents (9, 10). Indeed, the peak circulating serum concentrations of conjugates were only in the same range as their in vitro IC50 values and, thus, capable of eliminating at best only about 50% of tumor cells.These observations have led us (11, 12) and others (13, 14) to conclude that the previous attempts at delivering therapeutic doses of cytotoxic drugs via monoclonal antibodies have met with little success in clinical trials because of inappropriate choices of drug. We concluded that immunoconjugates must be composed of drugs possessing ...

N901-bR is an immunotoxin with potential clinical activity in SCLC. N901-bR is well tolerated when given by 7-day continuous infusion at the dose of 30 microg/kg(LBW)/d. Neurologic and cardiac toxicity were acceptable when given to patients with refractory SCLC. A second study to evaluate this agent after induction chemoradiotherapy in both limited- and extensive-stage disease was started following completion of this study.

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