Sandrine Faivre

Supraadditive effect of 2′,2′-difluorodeoxycytidine (gemcitabine) in combination with oxaliplatin in human cancer cell lines

Purpose: This study assessed the cytotoxic effects of the nucleoside analog gemcitabine in combination with the diaminocyclohexane platinum compound oxaliplatin. Methods: Growth inhibition studies were performed using the human CEM leukemia cell line and the colon-cancer cell lines HCT 116 and Colo 320 DM. Gemcitabine-oxaliplatin combinations were compared with gemcitabine-cisplatin combinations in the same cell lines using similar experimental settings. Cells were exposed for 2 h to gemcitabine and then for 24 h to oxaliplatin or cisplatin, and vice versa. Results: The 50% inhibitory concentrations (IC50 values) in single-drug experiments using 2 h of exposure to gemcitabine and 24 h of exposure to oxaliplatin or cisplatin were, respectively, 89 pM, 11.1 μM, and 10.3 μM for CEM cells; 46 pM, 10.2 μM, and 2.7 μM for HCT 116 cells; and 102 pM, 4.6 μM, and 8.6 μM for Colo 320 DM cells. Gemcitabine-oxaliplatin combinations displayed supraadditive effects in human leukemia and colon-cancer cell lines. The sequence of gemcitabine followed by oxaliplatin was more effective than the opposite sequence in HCT 116 and Colo 320 DM colon-cancer cell lines, whereas the sequence of oxaliplatin followed by gemcitabine yielded to synergistic effects in CEM cells. The cytotoxic effects of gemcitabine-oxaliplatin combinations were better than (HCT 116 cells) or equal to (CEM and Colo 320 DM cells) those of gemcitabine-cisplatin combinations. Conclusion: Our data show that the combination of gemcitabine with oxaliplatin exerts potent antiproliferative effects in human leukemia and colon cancer cells, warranting further investigations in the framework of phase I–II trials as an alternative for the treatment of solid malignancies.

Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies

AIM Phase I study of seliciclib (CYC202, R-roscovitine), an inhibitor of cyclin-dependent kinases 2, 7 and 9, causing cell cycle changes and apoptosis in cancer cells. PATIENTS AND METHODS This phase I trial aimed at defining the toxicity profile, the maximum tolerated dose (MTD), the recommended phase II dose (RD) and the main pharmacokinetic and pharmacodynamic parameters of oral seliciclib. Three schedules were evaluated: seliciclib given twice daily for 5 consecutive days every 3 weeks (schedule A), for 10 consecutive days followed by 2 weeks off (schedule B) and for 3d every 2 weeks (schedule C). RESULTS Fifty-six patients received a total of 218 cycles of seliciclib. Dose-Limiting Toxicities (DLT) consisting of nausea, vomiting, asthenia and hypokalaemia occurred at 1600 mg bid for schedule A and in schedule C, DLT of hypokalaemia and asthenia occurred at 1800 mg bid. The evaluation of longer treatment duration in schedule B was discontinued because of unacceptable toxicity at lower doses. Other adverse events included transient serum creatinine increases and liver dysfunctions. Pharmacokinetic data showed that exposure to seliciclib and its carboxylate metabolite increased with increasing dose. Soluble cytokeratin 18 fragments allowed monitoring of seliciclib-induced cell death in the blood of patients treated with seliciclib at doses above 800 mg/d. One partial response in a patient with hepatocellular carcinoma and sustained tumour stabilisations were observed. CONCLUSIONS The MTD and RD for seliciclib are 1250 mg bid for 5d every 3 weeks and 1600 mg bid for 3d every 2 weeks, respectively.

A risk-benefit assessment of amifostine in cytoprotection.

Recent advances in chemotherapy have focused on the benefit of high dose regimens, increasing the dose intensity of conventional chemotherapy and using intensified chemotherapy with or without autologous bone marrow rescue. Dose intensity usually increases objective response rates of antineoplastic drugs and might, in some circumstances, improves survival. However, unacceptable acute and/or cumulative toxicity often impairs the proper management of patients, leading to dose reduction or treatment delay, thus reducing the efficacy and potentially the quality of life of patients. Therefore, considerable efforts have been made to manage, to prevent, and to delay many acute and cumulative treatment-related toxicities.Amifostine (WR-2721) is a multiorgan cytoprotector which has demonstrated cytoprotective effects, in vitro and in vivo, against the most common cytotoxic drug-related toxicities and against radiation-induced adverse effects in healthy tissues. In vitro and in vivo, cytoprotection was observed in several organs including kidney, haematopoietic stem cells, myocardial cells, neural cells, and mucosa, without detectable protection of malignant cells. In addition, in preclin-ical studies, amifostine appeared to be able to reduce the risk of radiation-induced secondary neoplasms. Phase I studies showed that nausea/vomiting and hypotension are the dose-limiting toxicities of amifostine and these may be controlled by reducing the duration of injection of amifostine. Phase II and randomised studies have confirmed the efficacy of amifostine in protecting against radiotherapy-induced mucositis, cisplatin-induced nephrotoxicity, cyclophosphamide-induced neutropenia and carboplatin-induced thrombocytopenia. Importantly, the cytoprotection of healthy tissues occurred without any significant deleterious effect on response rate, time to progression, and survival of patients receiving amifostine.However, in addition to the potential quality of life benefit, the most important question of whether the use of a cytoprotective agent might translate into the possibility of maintaining the dose intensity of anticancer therapies has still to be answered. The real benefit of amifostine in the overall management of patients with cancer requires additional studies to determine whether this chemoprotective approach can be of benefit to patients by increasing response rate, time to progression, and long term survival in patients receiving the more recent combination therapies involving new drugs such as the taxanes and oxaliplatin.

Les inhibiteurs des récepteurs de l’Epidermal Growth Factor (EGF)

Resume Propos. – Les tyrosines kinases sont des proteines impliquees dans la proliferation cellulaire normale et dans la transformation maligne. Parmi les recepteurs tyrosines kinases les mieux etudies se trouve l’ Epidermal Growth Factor Receptor (EGFR), qui est exprime de maniere ubiquitaire en particulier par les cellules epitheliales et dans de nombreux carcinomes. EGFR est donc une cible potentielle des traitements anticancereux. Activites et points forts. – Les inhibiteurs d’EGFR actuellement en phase d’investigation clinique sont des anticorps agissant au niveau de la partie extracellulaire du recepteur (Cetuximab®) ou des petites molecules agissant au niveau de la partie intracytoplasmique du recepteur en bloquant le site de liaison de l’ATP des tyrosines kinases (Iressa®, Tarceva®). Les etudes de phase I ont montre que ces molecules semblent avoir un profil pharmacocinetique et pharmacodynamique favorable, avec une excellente tolerance et une administration aisee. Leur efficacite est actuellement testee dans des etudes de phase II et III. Perspectives et projets. – Les donnees cliniques actuelles suggerent que ces agents presentent une activite interessante dans plusieurs types de tumeurs solides, seules ou en association avec des agents plus conventionnels (chimiotherapie ou radiotherapie). Si ces resultats sont confirmes dans des etudes portant sur un plus grand nombre de patients, ces molecules pourraient etre des agents de choix en association avec une chimiotherapie, une radiotherapie ou en combinaison avec d’autres agents comme des inhibiteurs du cycle cellulaire ou des anti-angiogeniques.

Effects of adjuvant chemotherapy on the natural history and likelihood of therapeutic efficacy in advanced breast cancer patients: a critical literature review

The management of breast cancer has undergone major changes over the last three decades. Earlier diagnosis, through increasing awareness and public education coupled with the increased availability of mammographic screening, has resulted in an increasing proportion of patients with small tumours and negative axillary lymph nodes (1). Surgical treatment of locally confined breast cancer has become organ sparing and conservative, while the adjuvant treatment of breast cancer with systemic chemotherapy and/or hormonotherapy is now indicated for most patients with early stage disease. Reliable and clinically relevant assays for the presence of hormone receptors on tumours became available simultaneously with the development of tamoxifen. Ablative hormone therapy in pre