Targeting ErbB2 and ErbB3 with a bispecific single-chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro.

Inappropriate signalling through the EGFR and ErbB2/HER2 members of the epidermal growth factor family of receptor tyrosine kinases is well recognised as being causally linked to a variety of cancers. Consequently, monoclonal antibodies specific for these receptors have become increasingly important components of effective treatment strategies for cancer. Increasing evidence suggests that ErbB3 plays a critical role in cancer progression and resistance to therapy. We hypothesised that co-targeting the preferred ErbB2/ErbB3 heterodimer with a bispecific single-chain Fv (bs-scFv) antibody would promote increased targeting selectivity over antibodies specific for a single tumour-associated antigen (TAA). In addition, we hypothesised that targeting this important heterodimer could induce a therapeutic effect. Here, we describe the construction and evaluation of the A5-linker-ML3.9 bs-scFv (ALM), an anti-ErbB3/ErbB2 bs-scFv. The A5-linker-ML3.9 bs-scFv exhibits selective targeting of tumour cells in vitro and in vivo that co-express the two target antigens over tumour cells that express only one target antigen or normal cells that express low levels of both antigens. The A5-linker-ML3.9 bs-scFv also exhibits significantly greater in vivo targeting of ErbB2'+'/ErbB3'+' tumours than derivative molecules that contain only one functional arm targeting ErbB2 or ErbB3. Binding of ALM to ErbB2'+'/ErbB3'+' cells mediates inhibition of tumour cell growth in vitro by effectively targeting the therapeutic anti-ErbB3 A5 scFv. This suggests both that ALM could provide the basis for an effective therapeutic agent and that engineered antibodies selected to co-target critical functional pairs of TAAs can enhance the targeting specificity and efficacy of antibody-based cancer therapeutics.

Effects of systemic hyperthermia on the growth patterns of experimental neoplasms.

Hyperthermia has been shown to have a detrimental effect on experimental and human neoplasms. A water bath immersion system is described to evaluate the effects of systemic hyperthermia (SH) on the growth patterns of the Morris hepatoma 7777 in male Buffalo rats. SH and anesthesia were observed to have no long-term detrimental effects on weight trends or chow consumption. Inhibition of growth was demonstrated for this experimental tumor model at extreme SH (41.5 degree to 42.0 degree C), and it was statistically different (P less than 0.01) from the patterns of tumor growth observed in controls and tumor-burdened animals treated with moderate SH (39..5 degree to 40.0 degree C). Cessation of extreme SH resulted in acceleration of tumor growth so that no difference in tumor volume or animal survival was identified SH resulted in retardation of tumor growth patterns, but its effects were not sustained once treatments were stopped.

Diagnostic and therapeutic efficiency in croup and epiglottitis.

Croup and epiglottitis continue to be potentially life-threatening diseases in children. Early distinction is imperative as definitive treatment differs significantly. To determine the correlation of various clinical features, x-rays, and laboratory tests with diagnosis and management planning, a retrospective chart analysis of 194 children with croup (N = 169) and epiglottitis (N = 25) was performed. The clinical history and physical findings were most important in differential diagnosis. Patient age, lateral neck x-ray, and white blood count (WBC) strongly correlated with diagnosis. Counter immunoelectrophoresis (CIE) results did not alter therapy. No blood cultures were positive unless the patient had: WBC over 15,000 with more than 10 stabs, WBC over 20,000, or WBC with more than 20 stabs. Ampicillin resistant H. influenzae occurred in 21% of positive blood cultures. Capillary blood gases did not correlate with clinical need for intubation. It is suggested that a selective evaluation of patients with epiglottitis and croup can be performed in a more cost-effective manner without sacrifice in patient care.

Paragangliomas of the head and neck.

The medical records of 64 patients with paraganglioma of the head and neck seen between 1954 and 1984 at the University of Texas M.D. Anderson Hospital, Houston, were reviewed. Lesions were found in the carotid body (n = 24), jugulotympanic area (n = 37), vagal nerve (n = 4), and larynx (n = 1). A hereditary pattern was identified in six patients (9%). Metastases developed and caused the death of two patients (8%). No functional secreting tumors were identified. Paragangliomas are often misdiagnosed, both clinically and pathologically. Angiography is the definitive clinical study for diagnosis and treatment planning. Computed tomographic scanning further defines extent of the disease. Lesions in the neck are effectively treated by surgery. Jugulotympanic tumors can be successfully managed by surgery, radiation therapy, or a combination of both depending on the size and extent of the tumor. Secondary treatment of residual disease can be as effective as primary treatment.

Squamous cell carcinoma of the upper aerodigestive tract in nonusers of tobacco.

Nine hundred forty-five patients with squamous cell carcinoma of the upper aerodigestive tract (SCC-UADT) were treated at three University of Louisville-affiliated hospitals from 1970 through 1979. Retrospective analysis disclosed that 33 patients (3.4%) never used tobacco. This group offers interesting contrasts to the more prevalent tobacco-related epidermoid cancers. Cancers in nonusers of tobacco (mean age, 68 years) occurred approximately 10 years later than most epidermoid UADT cancers. Women predominated with a ratio of 2.7 to 1. Fifteen of 16 patients (94%) older than 70 years were women. Twenty-four of 33 primary lesions (72%) were in the oral cavity and two thirds of these were staged 0, I, and II (American Joint Commission [AJC]). Of the patients younger than 70 years of age, 42% were men, 42% had non-oral primaries, and most (74%) had advanced disease in AJC Stages III and IV. Second squamous cell primaries of the UADT developed in 6 of the 33 patients (18%) with an average of 48 disease-free months. Five of six were oral lesions in patients with original oral primaries. Of the 16 patients older than 70 years with small, localized oral cancers, conservative surgery failed in 9 (56%). Although 4 were salvaged by re-excision or radiation, 5 of these 16 patients in AJC Stage 0, I, and II died of this cancer (32%). The tendency for conservative initial surgical treatment in older patients is believed to be responsible for the higher than expected rate of treatment failure. An aggressive approach is recommended and further supported by the complete absence of surgical mortality in this group of patients.

Assessment of the aversive consequences of acute and chronic administration of the melanocortin agonist, MTII.

BACKGROUND: The synthetic melanocortin (MC) agonist, melanotan-II (MTII), reduces food intake and body weight for hours to days after administration. One early report on the effect of MTII suggested that part of its anorexic action may be mediated by aversive consequences. In that experiment, MTII was found to support a mild conditioned taste aversion (CTA). OBJECTIVE: The present experiments replicate and extend those findings in two additional CTA paradigms to further characterize the aversive effects of MTII in rats. METHODS: Experiment 1 simultaneously assessed the ability of MTII to support CTA and reduce food intake, using a small oral infusion of a novel taste as the conditioned stimulus. Experiment 2 assessed the aversive consequences of chronic MTII administration. To accomplish this, we paired implantation of lithium chloride (LiCl)-, MTII- or saline-containing osmotic minipumps with a constantly available novel flavor. After 7 days, rats received a choice test between the minipump-paired flavor and a previously available neutral flavor. RESULTS: Rats with saline minipumps exhibited no preference for either flavor. By contrast, rats in both the LiCl and MTII minipump groups significantly preferred the neutral flavor, indicating the development of a CTA. Additionally, CTA produced by administration of MTII was found to be more resistant to extinction than that produced by LiCl. CONCLUSIONS: The reduction in food intake caused by MTII is accompanied by aversive consequences regardless of route of administration. These results present difficulties for the development of MCs-based therapies for obesity.