Clinical evidence of efficient tumor targeting based on single-chain Fv antibody selected from a combinatorial library.

We present a system for cancer targeting based on single-chain Fv (scFv) antibodies selected from combinatorial libraries, produced in bacteria and purified by using an engineered tag. Combinatorial libraries of scFv genes contain great diversity, and scFv antibodies with characteristics optimized for a particular task can be selected from them using filamentous bacteriophage. We illustrate the benefits of this system by imaging patients with carcinoembryonic antigen (CEA)-producing cancers using an iodine-123 labeled scFv anti-CEA selected for high affinity. All known tumor deposits were located, and advantages over current imaging technology are illustrated. ScFvs are produced in a cloned form and can be readily engineered to have localizing and therapeutic functions that will be applicable in cancer and other diseases.

Antibody-directed enzyme prodrug therapy: efficacy and mechanism of action in colorectal carcinoma.

In antibody-directed enzyme prodrug therapy, an enzyme conjugated to an antitumor antibody is given i.v. and localizes in the tumor. A prodrug is then given, which is converted to a cytotoxic drug selectively in the tumor. Ten patients with colorectal carcinoma expressing carcinoembryonic antigen received antibody-directed enzyme prodrug therapy with A5B7 F(ab')2 antibody to carcinoembryonic antigen conjugated to carboxypeptidase G2 (CPG2). A galactosylated antibody directed against the active site of CPG2 (SB43-gal) was given to clear and inactivate circulating enzyme. A benzoic acid mustard-glutamate prodrug was given when plasma enzyme levels had fallen to a predetermined safe level, and this was converted by CPG2 in the tumor into a cytotoxic form. Enzyme levels derived from quantitative gamma camera imaging and from direct measurements in plasma and tumor biopsies showed that the median tumor:plasma ratio of enzyme exceeded 10000:1 at the time of prodrug administration. Enzyme concentrations in the tumor (median, 0.47 units g(-1)) were sufficient to generate cytotoxic levels of active drug. The concentration of prodrug needed for optimal conversion (Km) of 3 microM was achieved. Prodrug conversion to drug was shown by finding detectable levels of drug in plasma. There was evidence of tumor response; one patient had a partial response, and six patients had stable disease for a median of 4 months after previous tumor progression (one of these six had a tumor marker response). Manageable neutropenia and thrombocytopenia occurred. Conditions for effective antitumor therapy were met, and there was evidence of tumor response in colorectal cancer.

A staff support mechanism: the transformational partnership.

There have been many changes in nursing over the past decade, e.g. the movement of nursing education into higher educational sectors and the generation of many new nursing roles. The development of senior roles within nursing could potentially lead to isolation and, consequently, there may be calls for complementary support mechanisms. A transformational partnership is advocated, whereby nurses working in different organizations/specialties can provide mutual support. Existing support mechanisms for senior nursing can be variable and a transformational partnership can complement these as well as providing mutual clinical support. There are many advantages to this form of partnership which include professional and personal development as well as time out to reflect on practice. It requires commitment to the validity of the concept of professional support across traditional boundaries. A framework based on Holt's (1994) change theory is suggested as a method of implementing this initiative more widely within neighbouring organizations.

The importance of measuring quality of life in phase I/II trials of cancer therapy--the effects of antibody targeted therapy: Part I.

Phase I/II trials of new cancer therapies are designed to determine safety, efficacy and the optimal regimen for treatment. In order to uphold the principle that 'the interests of the subject must prevail over the interests of science and society' as laid down in the Declaration of Helsinki the effects of these trials on quality of life must be determined. Antibody-targeted therapies are a new form of cancer therapy designed to selectively deliver cytotoxic agents to cancer cells. Twenty-four patients with advanced colorectal cancer were enrolled into trials of three different treatment modalities based on this theme. Quality of life was measured using the Hospital Anxiety and Depression Scale and the Rotterdam Symptom Checklist prior to and 4 weeks after treatment. The Common Toxicity Criteria of the NCI were used to assess treatment related toxicity. There was no significant difference between pre- and post-treatment scores for all three treatment modalities. There was also no significant correlations between toxicity and physical or psychological morbidity. We suggest that the quality of life of patients undergoing phase I/II clinical trials with antibody targeted therapies for metastatic colorectal carcinoma was not adversely affected. We feel that in part this can be attributed to the high level and the intensity of support provided for the patients undergoing these treatments.