Chemotherapy cytotoxic potentiation

Nicotinamide potentiates the cytotoxic effects of chemotherapy and radiation treatment against tumor cells. This effect is probably attributable to increased... 

Spatial cooperation is a term coined to describe a situation when disease in one particular anatomic site is missed by one modality but is treated adequately by another. The essence of this is that radiation is a local therapy that will not impact on metastatic disease beyond the planned field borders. Systemic cytotoxic chemotherapy is traditionally used to address the potential distant spread of cancer. In the original description of this mechanism there is no assumption of an interaction between the drugs and radiation with the idea being that the best radiation and best chemotherapy be administered independently of toxicities. The classic example used in several textbooks to illustrate this is the treatment of childhood leukemia with systemic chemotherapy, while their central nervous system, a potential sanctuary site where disease is not treated adequately by chemotherapy, is treated by radiation (28). The reality of the interaction between radiation and chemotherapy is that the dose and timing of radiation are adjusted accordingly to minimize their impact on the neural tissues. 

Besides their utilization in the production of many compounds with therapeutic, diagnostic, and immunizing applications, animal cell cultures have undoubted utility in the performance of in vitro cytotoxicity tests. They can be used for the evaluation of potential anti-neoplastic agents and assessment of the safety of various products, such as pharmaceuticals, cosmetics, alimentary additives, pesticides, and industrial chemical products. Cell culture systems are frequently employed in the cancer chemotherapy field, in which their potential value for viability and cytotoxicity tests is largely accepted. Animal models play an important role in toxicity testing, but the pressure to adopt in vitro tests is growing since they present considerable economical advantages over in vivo tests. The use of animal models is limited to human metabolism studies, and there are... 

Whereas small molecules employ p450 activation/inhibition profiles to elucidate metabolic interactions/antagonisms, there is no comparable tool to model the potential interactions of multiple biologies or between biologies and cytotoxics. To assess potential interactions between a protein therapeutic and cytotoxic chemotherapy SOC, one approach is to conduct a single-dose PK interaction study to assess the impact of the protein therapeutic on the PK of the SOC cytotoxics in a pharmacologically relevant species (Table 25.2 [7,8]). The objective of these studies is to determine whether the protein therapeutic has an effect on the PK, particularly the peak concentration (Cmax) and/or time of peak concentration (Tmax) that might result in potentiation of the toxicity of the cytotoxic, or reduced efficacy associated with decreased exposure. 

Cloning of growth factor genes and recombinant DNA technology allow the large-scale production of cytokines for clinical use. Growth factors are now available to stimulate both erythroid and myeloid cell lines. These factors are potentially useful whenever there is cytopenia, whether due to disease or to cytotoxic chemotherapy. 

Alkylating agents. Busulfan is a radio-mimetic cytotoxic agent that is effective in PRV, reducing vascular events and delaying myelofibrosis. Its mutagenic potential should restrict its use to older patients. Chlorambucil and combination chemotherapy should be avoided because of excessive leukaemogenic risk. 

According to the FDA classification, the potential therapeutic benefits of vinca alkaloids have to be outweighed with the potential teratogenic risks (FDA classification D). All women of childbearing potential should be advised to avoid becoming pregnant while receiving cytotoxic cancer chemotherapy (80). 

Some phenothiazines, the so-called half-mustard type, stimulated T-cell blast formation, presented a natural killer cell activity, via possibly the activation of monocytes and macrophages, and an antibody-dependent cellular cytotoxicity of human peripheral blood mononuclear cells, and also showed cytotoxicity against several human cancer cell lines. These phenothiazines also might induce an in vivo antimicrobial activity by possibly their host-mediated immuno-potentiation [146]. Phenothiazines did not demonstrate any apparent mutagenic activity, but they were rather antimutagenic. These data suggest the possible applicability of half-mustard type phenothiazines and benzo[a]phenothiazines to cancer chemotherapy. 

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