Neuroblastoma, chemotherapy

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. 

This is an unusual drug in that it contains a metal atom, platinum (Pt) in this case. Cisplatin reacts with DNA to cross-link bases, disrupting normal DNA structure and function. This agent has found broad use in cancer chemotherapy, including efficacy in tumors of the testis, ovary, bladder, head and neck, thyroid, cervix, and endometrium. It is also active against neuroblastoma and osteogenic sarcoma. 

Table 7. Combined chemotherapy and photodynamic therapy of A/J mice bearing Neuro 2A neuroblastoma tumors using HPMA copolymer conjugates (from [42])...

Das, B., Yeger, H., Baruchel, H., Freedman, M., Koren, G., and Baruchel, S. (2003). In vitro cytoprotective activity of squalene on a bone marrow versus neuroblastoma model of cisplatin-induced toxicity Implications in cancer chemotherapy. Eur. f. Cancer 39, 2556-2565. 

G is a 7-year-old boy with neuroblastoma receiving chemotherapy. He is currently neutropenic and is febrile at 38.2°C. His physicians would like to empirically cover him for Pseudorrmnas aeruginosa with two agents and he is started on cefepime and an aminoglycoside. Which aminoglycoside would be the best choice ... 

Peroxide may be the greatest breakthrough we ve ever had for brain tumors. Surgery destroys brain tissue, and chemotherapy for brain neoplasms is just plain quackery. Neuroblastoma cells, a virulent brain cancer, were inhibited by H202 in lab experiments.3... 

Gallo G, Giarnieri E, Bosco S, et al. Aberrant bcl-2 and bax protein expression related to chemotherapy response in neuroblastoma. Anticancer Res. 2003 23 777-784. 

FIGURE 2.2 Methylation-specific PCR (MSP) analysis of the MDR-1 gene promoter methylation in human neuroblastoma (NB) cell lines (procured from Children s Oncology Group [COG] Philadelphia, PA) established from patients after chemotherapy.Methylation status of MDR-1 gene is represented as unmethylated (U) and methylated (M) in each cell type. A total of 19 neuroblastoma cell lines ° were examined by MSP and data indicate hypomethylation of MDR-1 gene in all cell lines tested. Hypomethylation (U) of MDR-1 gene indicates its increased expression and development of resistant phenotype in neuroblastoma cells after intensive chemotherapy. 

Another report provides data that HCMV infection could contribute to the reduced sensitivity of tumor cells to chemotherapy by induction of the cellular Bcl-2. HCMV infection of a human neuroblastoma cell line was shown to render the cells less sensitive to cytotoxic agents. These effects were associated with increased levels of Bcl-2 and decreased ability of the cells to undergo apoptosis. After antiviral treatment of the cells with ganciclovir the cells became again sensitive to cytotoxic agents, the Bcl-2 levels normalized, and apoptosis was inducible to the same degree as in the uninfected parental cell line (Cinatl et al. 1998). 

Laminas (LMN-ACO) serve as scaffolds for the anchoring of nuclear chromatin. Neuroblastoma cells with lamina genes deleted and lacking nuclear lamina, fail to differentiate in response to retinoic acid treatment. Lamina-defective neuroblastoma xenografts released cells with accelerated locomotion lamina-free tumor cells formed large tumors rapidly, and exhibited resistance to chemotherapy (doxorubicin, etoposide, paclitaxel). Laminary structures in place were necessary for organ differentiation [1627]. 

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