Biochemical and biological activity of the anthracycline analog, 4-demethyl-6-0-methyl-doxorubicin

Summary The chromophore-modified derivative of doxorubicin, 4-demethyl-6-0-methyl-doxorubicin, has been tested for antitumor activity in a range of experimental murine tumor systems. In contrast to the inactive 6-0-methyl derivative of daunorubicin, 4-demethyl-6-0-methyl-doxorubicin provided antitumor effects comparable to that of the parent compound. In addition, detailed DNA-interaction studies showed that the doxorubicin derivative retains the ability to bind DNA by the intercalation mechanism. However, the binding affinity was appreciably reduced following structural modification in the anthraquinone chromophore. On the basis of the proposed models of intercalation, these results could be rationalized in terms of steric influence of the bulky methoxy group. The results of this study are in agreement with the correlation already observed between DNA binding and relative antitumor activity of anthracyclines.     

One-day therapy for treatment ofHelicobacter pylori infection

The present study evaluated the effect of a one-day high-dose combined therapy onHelicobacter pylori infection. Thirty-two consecutive patients (suffering from either peptic ulcer or nonulcer dyspepsia) withHelicobacter pylori infection received omeprazole (40 mg) +bismuth subcitrate (240 mg×4)+amoxicillin suspension (2000 mg×4)+metronidazole (500 mg×4), for only one day. Endoscopy, histology, culture, and susceptibility studies were done at entry and 30 and 90 days after the treatment day. Successful eradication was obtained in 23/32 (72%) patients and gastritis had resolved in 95% of these. Side effects were induced by the treatment in 6/32 (19%) patients, but these were all self-limiting, short-lasting, and did not require any specific treatment. Development of bacterial resistance to metronidazole occurred in 6/9 (67%) non-eradicated patients. These data suggest that one-day treatment with high doses of amoxicillin, metronidazole, bismuth, and omeprazole represents an effective, safe, and inexpensive therapeutic approach for the treatment ofH. pylori infection.     

Establishment and characterization of xenografts and cancer cell cultures derived from BRCA1 -/- epithelial ovarian cancers

The BRCA1 gene is responsible for a high number of hereditary breast and ovarian cancers that cluster in families with a strong genetic predisposition. Despite intense investigation, the accumulating findings on BRCA1 biological functions have not yet been translated into specific therapeutic approaches, also due to the lack of suitable experimental models. The purpose of this study was to establish and characterize cell cultures and xenografts from patients with BRCA1 -/- ovarian cancers. We derived two ovarian cancer cell lines, termed PD-OVCA1 and PD-OVCA2, both from patients previously treated with chemotherapy, that propagate in SCID mice as well as in vitro for a limited number of passages. Both cell lines expressed cytokeratins and the CA125 tumour marker. A detailed molecular characterization highlighted both constitutive and somatic genetic events that abrogate BRCA1 gene function. Both cell lines were shown to lose the wild type BRCA1 allele; intriguingly, these deletions were apparently accompanied by gain of one or more copies of the mutant alleles. Finally, a genomic profile of major chromosomal aberrations was obtained by the Multiplex Ligation-dependent Probe Amplification (MLPA) technique, which disclosed chromosomal imbalances targeting specific genes in each cell line. The PD-OVCA1 and PD-OVCA2 ovarian cancer cell lines will provide a valuable tool for new experimental models for the study of BRCA1-associated tumour biology.     

Phase II study of irinotecan and docetaxel in patients with previously treated non-small cell lung cancer: an Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 007)

This study was designed to evaluate the activity and tolerability of irinotecan and docetaxel in patients with previously treated non-small cell lung cancer (NSCLC). Eligibility included recurrent or progressive NSCLC, previous chemotherapy, age > or = 18 years, ECOG PS < or = 2. Treatment consisted of irinotecan (160 mg/m2 i.v.), followed by docetaxel (65 mg/m2 i.v.) on day 1 of a 21-day cycle, for a maximum of 6 cycles. Forty patients were enrolled. Median age was 60 years and median ECOG PS was 1. All patients were evaluable for toxicity and 31 (78%) were evaluable for response. A total of 125 cycles was administered (median, 3; range, 1-6). Most common grade 3-4 toxicities were neutropenia (62%), neutropenic fever (22%), and diarrhea (32%). Response rate was 10%; a further 40% of patients achieved stable disease. All responses were observed in patients with ECOG PS < or = 1, age <70 years, and who had received only one prior chemotherapy regimen. Median time to progression was 2.8 months and median survival was 7.4 months. Because of significant toxicity and limited activity, further investigation of irinotecan plus docetaxel in second line NSCLC is not recommended.     

Sequential treatment with exemestane and non-steroidal aromatase inhibitors in advanced breast cancer

BACKGROUND: The steroidal aromatase inactivator exemestane has demonstrated activity after prior failure of non-steroidal aromatase inhibitors (including third-generation inhibitors letrozole and anastrozole) in postmenopausal women with advanced breast cancer. If exemestane is used as first anti-aromatase agent, however, it is unclear whether patients can still benefit from letrozole or anastrozole after progression. PATIENTS AND METHODS: Postmenopausal patients with advanced, hormone receptor-positive or -unknown breast cancer were eligible for this study. Patients with no prior exposure to anti-aromatase drugs received exemestane, 25 mg daily, as first anti-aromatase agent. At the time of progression, patients were crossed-over to anastrozole or letrozole if further endocrine therapy was considered appropriate. Patients with prior exposure to anti-aromatase agents were also included in the study, and were given anastrozole or letrozole if they had previously received exemestane, or exemestane if they had previously received anastrozole or letrozole. The primary endpoint of the study was the clinical benefit rate (complete response + partial response + stabilization of disease for >or=24 weeks). RESULTS: Forty patients received exemestane 25 mg daily as first anti-aromatase agent, with a CB rate of 67.5% (95% CI 52.9-82.0%) and a median time to progression (TTP) of 9.6 months. In 18 patients, letrozole (n = 17) or anastrozole (n = 1) were used after failure of exemestane: the CB rate was 55.6% (95% CI 32.6-78.5%) with a median TTP of 9.3 months. In 23 patients, exemestane was used after failure of letrozole or anastrozole: the CB rate was 43.5% (95% CI 23.2-63.7%) with a median TTP of 5.1 months. CONCLUSIONS: Our study confirms that exemestane is active after prior failure of letrozole or anastrozole. We have also shown that patients can receive exemestane as their first anti-aromatase agent and still benefit from letrozole or anastrozole after progression. This suggests that the partial non-cross resistance between steroidal and non-steroidal anti-aromatase agents is independent of the sequence employed.