Chemotherapy preclinical studies

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

Robertson JM, Shewach DS, Lawrence TS. Preclinical studies of chemotherapy and radiation therapy for pancreatic carcinoma. Cancer 1996 78(3 Suppl) 674—679. 

Preclinical studies of BCNU-polymer preparations proceeded in four systematic stages. The first series of experiments examined in vivo release kinetics of BCNU loaded polymers. The initial study involved EVAc copolymer implantation in the rat brain (31). Subsequent to polymer placement, a Brat-ton-Marshall assay measured BCNU concentrations in both cerebral hemispheres, and serum samples were collected at prescribed time points. The hemisphere ipsilateral to polymer placement corresponded with peak BCNU levels at 4 h clinically significant concentrations persisted at day 7. In contrast, both contralateral hemisphere and serum BCNU levels were at least an order of magnitude lower throughout the experiment. Thus, the study served as proof of principle of the ability of polymer technology to simultaneously achieve sustained release and local delivery of chemotherapy within the CNS. 

Anti-tumor activity of bevacizumab has been reported in various preclinical animal models (primary and metastatic) with a broad array of tumor types [106, 107]. Clinical studies have further validated the focal role of VEGF in cancer. A single infusion of bevacizumab at 5 mg/kg in patients with primary and locally advanced adenocarcinoma of the rectum demonstrated direct and rapid antivascular effect in human tumors, with decreases in tumor perfusion, vascular volume, microvascular density, and interstitial pressure [108]. Clinical efficacy of bevacizumab in combination with 5-FU- and irinotecan-based regimens has been demonstrated in patients with metastatic colorectal cancer a significant improvement in overall survival time was observed compared with chemotherapy alone (20.3 versus 15.6 months for chemotherapy plus bevacizumab versus chemotherapy alone) [109]. 

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