Karol Sikora

Comparison of dexamethasone and ondansetron in the prophylaxis of emesis induced by moderately emetogenic chemotherapy

A multicentre, randomised, double-blind, cross-over trial was done to compare the efficacy and safety of a serotonin receptor antagonist--ondansetron--and dexamethasone in the prophylaxis of acute and delayed emesis and nausea induced by moderately emetogenic non-platinum-containing chemotherapy regimens. Patients were treated as outpatients and received intravenous ondansetron 4 mg or dexamethasone 8 mg before chemotherapy and oral maintenance (ondansetron 4 mg every 6 h and dexamethasone reducing from 4 mg to 1 mg 6-hourly between days 1 and 5) for 5 days. 112 patients were treated (38 men, 73 women, 1 with no gender recorded; age range 30-73 years) and 100 were evaluable for cross-over analysis. Patients taking ondansetron or dexamethasone reported no significant difference in complete and major control of acute (83% vs 79%, p = 0.46) or delayed (82% vs 88%, p = 0.214) emesis (vomiting plus retches). Significantly more patients on dexamethasone (87%) than on ondansetron (72%) reported control of delayed nausea (days 2-5) (p = 0.003). Both drugs were well tolerated with no significant difference in the number of adverse events, and this is reflected by similar patient preference for ondansetron (40%) and dexamethasone (30%) (p = 0.244). Both drugs offer adequate out-patient control of chemotherapy-induced emesis; however, dexamethasone has an advantage in the control of delayed nausea, and also in terms of cost and resource allocation.

Gene therapy for cancer

Abstract The molecular basis of cancer is now understood to involve activation of dominant oncogenes and inactivation of tumour suppressor genes, and these genetic events may represent novel targets for cancer therapy. This review focuses on the potential use and ethical implications of gene transfer to alter the behaviour of somatic cells in cancer patients. Antisense nucleic acids and ribozymes represent informational drugs that may be used to modulate the expression of selected genes and suppress malignant behaviour in cancer cells. Genetic immunomodulation by introducing genes for cytokines into cancer cells or lymphocytes can stimulate a cytotoxic immune response against the tumour. Gene transfer techniques can be applied to target prodrug activation specifically to tumour cells and also to protect normal tissues against toxic chemotherapy. Gene replacement therapy could even be used to restore the function of defective tumour suppressor genes. Lancet 1992: 339: 715-21.

Genetic Prodrug Activation Therapy for Breast Cancer: A Phase I Clinical Trial of erbB-2–Directed Suicide Gene Expression

PURPOSE This trial was designed to test the safety and efficacy of a tumor-specific genetic prodrug activation therapy targeted by use of the human erbB-2 gene promoter. The erbB-2 oncogene is overexpressed in approximately 20% of cases of breast cancer and is associated with poor prognosis. PATIENTS AND METHODS Twelve breast cancer patients received transcriptionally targeted gene therapy in a phase I clinical trial using direct intratumoral injection of plasmid construct combined with systemic administration of prodrug. The genetic prodrug activation therapy is specifically targeted to erbB-2-overexpressing breast cancer cells by use of a therapeutic cassette that contains the Escherichia coli cytosine deaminase gene driven by the tumor-specific erbB-2 promoter, thus allowing activation of fluorocytosine to the active cytotoxic fluorouracil only within tumor cells that express the oncogene. RESULTS The approach was shown to be safe and to result in targeted gene expression in up to 90% of cases. Using a number of different assays, we demonstrated that significant levels of expression of the suicide gene were specifically restricted to erbB-2-positive tumor cells, confirming the selectivity of the approach. CONCLUSION The results of this study, the first targeted gene therapy for breast cancer and the first to use the cytosine deaminase system in human subjects, are encouraging for the development of genetic prodrug activation therapies that exploit the transcriptional profile of cancer cells.

c-myc oncogene expression in colorectal cancer

The pattern of c‐myc gene organization and expression has been examined in resected colonic tumors and in the adjacent normal colon from 15 patients undergoing radical surgery. DNA hybridization showed no evidence of gene amplification or rearrangement. Transcripts of the c‐myc messenger ribonucleic acid (mRNA) were elevated up to 32‐fold in 12 of 15 tumors. The gene product, p62c‐myc, was detected by both immunoblotting and immunohistology using a monoclonal antibody raised against a synthetic peptide immunogen. There was close correlation between c‐myc mRNA copy number and p62c‐myc abundance. Three well differentiated tumors contained high levels of transcript and protein, whereas four poorly differentiated tumors had the lowest levels. The assay of oncogene products may provide new biologically relevant tumor markers for determining prognosis and guiding treatment.

Tumour inoculation during laparoscopy

ous infusion over 30 60 min. Treatment was uncomplicated, besides mild urticaria after the fourth dose, which quickly responded to antihistamines. There was temporary, subjective improvement after antibody therapy but the liver and spleen size did not change and the patient remained transfusiondependent. Over the next 3 months, she was treated with corticosteroids and cyclosporin; serum albumin and blood

A novel tumour marker related to the c-myc oncogene product

We have studied the utility of the c-myc oncogene product as tumour marker using a set of monoclonal antibodies raised against synthetic peptides constructed from sequence data of the human c-myc oncoprotein. One antibody, Myc1-9E10, raised against the C-terminal 32 amino acids, has been shown to detect specifically the 62 kDa c-myc gene product in tumour cells. Immunoblotting of sera and urine with this antibody consistently revealed a single 40 kDa band (p40). Quantitative analysis using dilution dot immunoblotting demonstrated a considerable increase in the titre of p40 in the sera of 51 patients with a wide range of advanced solid tumours when compared with 17 healthy controls and 50 patients with non-malignant diseases. Serial measurement of the p40 titre in 12 patients with resected colorectal carcinoma shows a gradual return to normal with a half-life of 7 days. Our data suggests that p40 may be a useful new marker for monitoring tumour activity.

The partial purification and characterization of GnRH-like activity from prostatic biopsy specimens and prostatic cancer cell lines

We have investigated the possibility of the secretion of gonadotrophin-releasing-hormone (GnRH)-like peptides by prostatic cancer cells in culture and their presence in cytosolic preparations from human prostatic biopsy specimens. A GnRH-specific radioimmunoassay showed GnRH-like activity in concentrated cytosolic preparations and conditioned media from DU 145, an androgen-insensitive human prostatic cell line and from LNCaP, an androgen-responsive prostatic cancer cell line. GnRH immunoreactivity in culture media correlated directly with cell numbers. HPLC demonstrated that this GnRH-like material co-migrated with synthetic GnRH. This homology between synthetic GnRH and partially purified prostatic GnRH was confirmed following V8 protease and trypsin digestion which resulted in similar alterations in HPLC characteristics. The mean content of GnRH-like activity/g specimen tissue was significantly more in malignant tissue (88.5 +/- 80.5 fmol) than in benign (29.6 +/- 22 fmol), though more specimens of benign tissue were positive (37/54) than malignant tissue (6/22). This observation, taken with an earlier finding of GnRH-specific receptors in a hormone-sensitive cell line and human cancer specimens provides supportive evidence for the autocrine hypothesis of cell regulation.

Genetic prodrug activation therapy

Genetic prodrug activation therapy shows promise as a therapeutic option for the treatment of cancer as well as a variety of other diseases. It involves the insertion of a gene encoding a drug-metabolizing enzyme into cells and the systemic administration of a prodrug. The prodrug is converted to a cytotoxic agent by the action of the expressed enzyme. To ensure that the enzyme is only expressed in the targeted subset of cells, the transcriptional apparatus of a gene that is unique to this subset is used to regulate the gene encoding the drug-metabolizing enzyme. As with all types of gene therapy, one of the major obstacles to successful clinical treatment is the development of safe and effective gene delivery systems.

Combined choriocarcinoma and yolk sac tumor arising in Barrett's esophagus

A patient with primary adenocarcinoma with yolk sac and trophoblastic differentiation occurring in Barretts esophagus is reported. Yolk sac differentiation at this site has not been described previously. The diagnosis of germ cell differentiation initially was suggested by the finding of elevated serum tumor marker levels. The patient experienced disease remission after cytotoxic chemotherapy.

Does interferon cure cancer

Since their discovery in 1957 the interferons have been extensively studied by virologists and molecular biologists. Their clinical use in preventing and treating viral disease has been recently reviewed in this journal.1 Shortly after their discovery it was noted that certain tumour cell lines grew more slowly in tissue culture in the presence of interferon.2 This was followed by the demonstration that interferon could decrease tumour growth in mice bearing experimental tumours.3 The comparison between mouse and human systems has continually been hampered by the apparent species specificity of interferon and by the different growth kinetics of experimental and human neoplasms. Interferon was first used against human cancer in France in 1963.4 Eleven patients with acute myeloid leukaemia were treated with a relatively impure leucocyte interferon preparation. A partial antitumour effect was noted in one of these patients. In the same year Dr Kari Cantell of the Central Public Health Laboratory in Helsinki began the large-scale purification of interferon from buffy coat leucocytes collected from blood for transfusion.5 The scale of production and the purity of the product have increased over the years. Most of the clinical pharmacokinetic, antiviral, and antitumour studies have been carried out with this product. In 1971 the first large-scale clinical trial of interferon in cancer was begun.6 It was given as adjuvant treatment to patients who had had limbs amputated for osteosarcoma. The initial results were promising, but, as will be shown, the absence of a randomised, concurrent control group makes their interpretation difficult. In 1974 the National Cancer Institute in Washington began trials with synthesised interferon inducers.7 Various compounds that stimulate the production of endogenous interferon are available. Toxicity limits the dose that can be administered and thus the serum concentrations of interferon achieved. Some 30