Antitumor drugs selective toxicity

Selection of agents for combination chemotherapy regimens involves consideration of drug-specific factors such as mechanism of action, antitumor activity, and toxicity profile. Drugs that possess minimally overlapping mechanisms of action and toxicities are combined, when possible. Myelosuppressive combinations are sometimes alternated with nonmyelosuppressive combinations to allow bone marrow re-... 

An important application of the trans effect is the synthesis of specific isomers of coordination compounds. Equation 1.3 and Equationl.4 show how the cis and trans isomers of Pt(NH3)2Cl2 can be prepared selectively by taking advantage of the trans effect order Cl > NH3, where L = Cl. This example is also of practical interest because the cis isomer is a very important antitumor drug (Section 16.5), but the trans isomer is toxic. 

Administration of some anticancer drugs by continuous infusion has been shown to improve their therapeutic index through selective reduction of toxicity with retained or enhanced antitumor efficacy. 

These results are clear evidence that sulfur reacts mainly directly with Pt amine compounds, substituting Cl-, without prior aquation. As is evident from Table IV, the hydrolyzed species [Pt(dien)(H20)]2+ will almost selectively react with 5 -GMP (3.6 Af-1 sec-1 versus 0.51 Af-1 sec-1 and 0.18 Af-1 sec-1), whereas the chloro species [Pt(dien)Cl]+ will only react with sulfur. This information is of extreme importance in the strategy of the development of new Pt drugs. If it would be possible to develop a compound with structural properties such that the direct attack by sulfur is inhibited, but with a similar rate of chloro hydrolysis compared to cis-Pt, this would lead to compounds with improved antitumor properties and lower toxicities. The data depicted in Table IV were obtained at pH 5. However, it has been proved that GS- reacts remark-... 

A number of animal model systems have been developed to provide tumor microenvironments that mimic the clinical situation. However, there are no perfect animal models for drug development. The adequacy of any specific animal model depends on its validity, selectivity, predictability, and reproducibility (22). In cancer chemotherapy, animal models are selected to simultaneously demonstrate antitumor efficacy and evaluate systemic toxicities in an intact organism. Ideally, the tumor system under study in the animal model should be genetically stable over time, with homogeneous characteristics that mimic human tumor biology. In oncology, a variety of diverse animal models for human tumors have been developed. These models can be broadly categorized in to three... 

Based on the novel structure and superior antitumor activity against LI210 leukemia, tyiocrebrine (2) was selected as a drug candidate and successfully proceeded to Phase I clinical trials in the early 1960s. However, the trials were eventually terminated in 1966 due to central nervous system (CNS) toxicity, primarily ataxia and disorientation. Too few patients were treated to establish the efficacy of 2. 

Anti-cancer drugs such as cyclophosphamide (15), aniline mustard, and nitrosoureas are transformed to reactive metabolites which are the toxic species required for their anti-cancer activity. Experiments with selectively deuterated analogs of these drugs has distinguished which pathway, among several alternative pathways of metabolism, is responsible for antitumor activity. For example, a deuterium isotope effect was observed for the formation of 4-ketocyclophosphamide (16), formed by the oxidation of the carbon alpha to the phosphoramide nitrogen, but there was no Isotope effect on the anti-tumor activity. However, there was a marked effect on the subsequent -elimination reaction and consequent decrease in anti-tumor activity by deuterium substitution at C-5. Thus, the formation of acrolein and phosphoramide mustard is rate determining for the anti-tumor activity of cyclophosphamide. 

The metal ruthenium possesses several favorable chemical properties and it may be a strong candidate to form a basis for rational anticancer drug design [104,105]. For instance, several ruthenium(II) and ruthenium(III) complexes (Scheme 5.5) exhibit a high antitumor activity both in vitro and in vivo [2,106,107]. Therefore, the reactions of Ru and Ru complexes with DNA and sulfur-containing amino acids as well as proteins has been studied by NMR and other spectroscopic methods (e.g. HPLC). Such studies may facilitate the development of an additional structure-activity relationship and allow more selective, potent and less toxic anticancer drugs to be designed. 

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