Anticancer agents evaluation

Figure 7.9 Other platinum-containing anticancer agents evaluated in clinical trials. (A) Oxaliplatin, Pt(II) (B) ZD0473, Pt(II) (C) iproplatin, Pt(IV) (D) ormaplatin, Pt(IV).

Geldof A.A., Mastbergen, S.C., Hemar, R.E., and Faircloth, G.T. (1999) Cytotoxicity and neuro-cytotoxidty of new marine anticancer agents evaluated using in vitro assays. Cancer Chemother. Pharmacol., 44, 312-318. This publication is devoted to didemnin B, aplidin and homoisohalichondrin B. 

Then, we evaluated the enzymatic activation of a second-generation dendritic prodrug with camptothecin (CPT), an anticancer agent, in place of the reporter groups (dendron 38). 

The initial strategy for Phase I is to conduct a single-dose safety study in normal volunteers. The first trial demands close 24-hour supervision in a clinical setting. Ethical considerations may, however, demand that only patients be used, for example, when evaluating an anticancer agent with predictable toxicity. A repeat dose tolerance and pharmacokinetic study in normal or patient volunteers is then conducted for chronically administered drugs. These studies will provide the necessary safety information to support efficacy testing. 

Flow cytometry (FCM) is widely used for exploring mechanism of action of compounds that compromise proliferation since it is rapid, accurate and usable for any cellular context [5], In this chapter we want to point out technical and strategic aspects of use of FCM for cell cycle studies of a putative anticancer agent. As an example we used Edotecarin, a topi inhibitor, firstly evaluating proliferation outcome and classical DNA content analysis by propidium iodide, and then since the compound treatment produced cell cycle perturbation difficult to interprete, a two-parametric analysis by 5-bromo-deoxyuridine (BrdU) was applied for separating cell cycle phases. Moreover we put our efforts into identifing specific cell cycle arrest not easily demonstrable by previously described methods, through the use of in vitro kinetics ( pulse and chase ). Finally, in vivo assessment of efficacy and biomarkers modulation after treatment was analyzed. 

Skipper, H.E., Schabel, R, and Wilcox W.S., Experimental evaluation of potential anticancer agents on the criteria and kinetics associated with "curability" of experimental leukemias. 

If the results following the in vitro evaluation of a macromolecular anticancer agent are promising, in vivo tests are then warranted. Animal tumor models are the status quo for the in vivo study of anticancer agents. An animal tumor model should be reproducible, have a low rate of spontaneous cures or remissions, and a low and nonvariable immunogenicity in the host. For tests of mechanisms that also occur in human tumors, the parameters involved in these mechanisms should be similar to those of human tumors [210],... 

In summary, the results obtained so far and reviewed here bode well for the future of polymers in the delivery of anticancer agents. A further systematic study of their advantages and limitations is necessary to evaluate fully their therapeutic potential. The final judgement, however, will come from the results of clinical trials. 

Advantages and Limitations of LCLs for Evaluating the Pharmacogenomics of Anticancer Agents... 

The authors are supported by the Pharmacogenetics of Anticancer Agents Research (PAAR) and the Comprehensive Research on Expressed Alleles in Therapeutic Evaluation (CREATE) groups within the NIH Pharmacogenetics Research Network (GM63340, GM61393). 

In our continuing search for potential anticancer agents, GL331 (4), which is currently in Phase Ha clinical trials, highlights our current study. However, in all, over the last several years, we have found more than 100 new cytotoxic antitumor compounds and their analogs with confirmed activity in the NCI in vitro human tumor cell lines bioassay. These compounds are of current interest to NCI for further in vivo evaluation and to us for further... 

Sarcophytols A (46) and B (47) are simple cembranoids isolated from the Okinawan soft coral S. glaucum and have been reported to possess potent inhibitory activities against various classes of tumor promoters.70 71 Sarcophytol A (46) mediated dose-dependent diminution of 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced transformation of JB6 cells.72 When evaluated for potential to inhibit TPA-induced JB6 cell transformation, several of the sarcophine metabolites (48 to 58) mediated inhibitory responses greater than sarcophytol A (46) or sarcophine (45), most notably 7a-hydroxy-y8(19) deepoxysarcophine (50), which was comparable to 13-cz s-retinoic acid. These studies provide a basis for further development of novel furanocembranoids as anticancer agents. 

Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10) 721-732 Semenza GL (2007) Evaluation of HIF-1 inhibitors as anticancer agents. Drug Discov Today... 

Duncan, R., P. Kopeckova-Rejmanova, J. Strohalm, I. Hume, H. C. Cable, J. Pohl, J. B. Lloyd, and J. Kopecek. 1987. Anticancer agents coupled1e(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates/itro. Br. J. Cancei55 165-174. 

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