Chemoprevention of tumors: the role of RAR-beta.

Chemoprevention can be defined as the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. The knowledge of carcinogenic mechanisms provides the scientific rationale for chemoprevention. Epithelial carcinogenesis proceeds through multiple discernible stages of molecular and cellular alterations. Understanding of the multistep nature of carcinogenesis has evolved through highly controlled animal carcinogenesis studies, and these studies have identified three distinct phases: initiation, promotion and progression. Animal model studies have provided evidence that the development of cancer involves many different factors, including alterations in the structures and functions of different genes. Transitions between successive stages can be enhanced or inhibited in the laboratory by different types of agents, such activities providing the fundamental basis for chemoprevention.

Liposomal doxorubicin (Caelyx) in advanced pretreated soft tissue sarcomas: a phase II study of the Italian Sarcoma Group (ISG).

BACKGROUND: Doxorubicin remains one of the few drugs with consistent single agent activity in advanced Soft Tissue Sarcomas (STS), with a demonstrated dose-response relationship. Liposomal-encapsulated Doxorubicin (LED) has been shown to be at least as active as free doxorubicin in experimental models, and phase I and II human studies indicate that this novel strategy of drug delivery my have less myocardial toxicity. Few clinical trials in adult STS have been published until now, with disappointing and often contrasting results. PATIENTS AND METHODS: Twenty-five consecutive patients with measurable advanced and/or metastatic STS, previously pretreated with anthracycline-based chemotherapy, were enrolled into the trial. LED (Caelyx) was administered over 1-hour intravenous infusion at the dose of 30 mg/m2 in the first 5 patients, then at the fixed dose of 50 mg/m2 in the subsequent 20 patients. Treatment was given on ambulatory basis, at 3-week intervals. Antiemetics were generally not required and only used if indicated. RESULTS: A total of 98 courses of chemotherapy were given (median 4 per patient, range 2 to 5). Amongst the 25 evaluable patients, there were 3 partial responses (12%, 95% confidence interval 4.2% to 29.9%) lasting 3-9+ months and all occurring in patients treated at 50 mg/m2/cycle. In addition, 2 minor responses (4+ months) and 17 stable disease (2-7+ months) were observed; the remaining 3 patients progressed while on therapy. The median delivered drug dose-intensity was 13.3 mg/m2/week (range 10 to 16.6 mg/m2/week). Treatment was well tolerated, with no patient requiring dose reduction or therapy delay because of toxicity. Only 2 cases of WHO grade 3 toxicity occurred, consisting of neutropenia and scrotal skin toxicity; respectively; no cardiotoxicity was seen. CONCLUSIONS: This study shows that Caelyx has some activity in advanced, anthracycline-pretreated STS, with favourable toxic profile. From the analysis of available experiences it emerges that liposomal doxorubicin has not been tested at doses adequate to exploit the antitumor effects of the drug, being the reached dose-intensity being even lower than those deemed critical for obtaining optimal responses to free doxorubicin. We suggest that further and better addressed studies be performed in STS, including patients with less advanced stages of disease, focused on attempting to delivery the drug at optimal doses.

Dose-intensive first-line chemotherapy with epirubicin and continuous infusion ifosfamide in adult patients with advanced soft tissue sarcomas: a phase II study.

This phase II study was designed to verify the activity and safety of an intensive epirubicin/ifosfamide schedule in untreated soft tissue sarcoma (STS) patients by using both the agents at the identified maximal tolerated doses. 39 adult patients were treated with epirubicin at 55 mg/m2, on days 1 and 2 (total dose per cycle 110 mg/m2) combined with ifosfamide at 2.5 g/m2 days 1-4 (total dose per cycle 10 g/m2), with equidose mesna uroprotection and G-CSF support. Treatment was given on an ambulatory basis, at 3-week intervals. The overall objective response (OR) rate was 59% (95% confidence interval, CI, 43-72%), with 5 complete responses (13%) at 18 partial responses (46%); 12 partial responders were rendered disease-free following surgery. The median survival time was 19 months, being 23 and 13 months, respectively, for responding and non-responding patients. The median time to response was 40 days (range 21-60). Treatment-related toxicity was overall acceptable. The OR of 59% was the highest ever reported in our consecutive studies in advanced STS, confirming that improved therapeutic efficacy can be obtained with intensified regimens in such a disease; both the response duration and survival were also longer. The observed activity proved to be interesting with regard to the high response rate in the lung (86%), as well as the proportion of patients rendered disease-free by early surgery after the achievement of a partial response (55%). Both these findings may be important in the multimodality approach to patients with lesions potentially resectable for cure.

Antiproliferative and synergistic effect of interferon alpha-2a, retinoids and their association in established human cancer cell lines.

The effect of 13-cis-retinoic acid (cRA) and all-trans-retinoic acid (tRA) used alone or in combination with interferon alpha-2a (alpha-IFN 2a) was tested on three established human cell lines: KB (epidermoid carcinoma of the oral cavity), SCC-25 (tongue squamous cell carcinoma) and MCF-7 (mammary carcinoma). Both retinoids significantly decreased cell proliferation (growth curves) and colony forming efficiency (CFE) in all cell lines, in a dose-dependent way (at a concentration ranging from 10(-5) to 10(-9) M) and differing from line to line, following the pattern: MCF-7 > SCC-25 > KB. Retinoids at any concentration (already at 10(-7) M) combined with alpha-IFN 2a (ranging from 100 to 500 IU/ml) were more effective in inhibiting cell proliferation than each of the two compounds alone. This was particularly evident with SCC-25 cells. Concerning MCF-7 cells, on the contrary, the effects produced by the association suggested a possible additive more than synergistic amplification of growth inhibition.