Medical brain Notes 3

  Some principles of cancer pharmacotherapy   Cancer therapy consists of surgery, irradiation, and chemotherapy. Cancer chemotherapy is particular and par-ticularly challenging in several aspects:   •       While in most cases the aim of pharmacotherapy is to modulate cell function, in cancer therapy it is to kill the diseased cells – no prisoners. Selective killing is quite feasible with bacteria, since they are prokaryotic, and their biochemical apparatus contains a substantial num-ber of targets that do not occur in human cells 1 . It is more challenging yet possible with fungi and parasites. The latter share with our own cells the eukaryotic nature, and so inhibitors of ribosomal protein synthesis, which are very important in antibacterial chemotherapy, are most-ly useless. However, fungi have ergosterol in their cell membranes instead of cholesterol, and both ergosterol and its synthesis are targeted by drugs that thus can be reasonably selec...

  Cell type-specific antitumor drugs Among the drugs used in cancer chemotherapy, we may broadly distinguish two functional groups:   1.    Cell-type specific drugs, and   2.    General cytotoxic drugs.   The availability of cell type-specific drugs is limited to se-lected tumours and depends on some specific traits the tu-mour cells have inherited from their differentiated, healthy ancestors. Most commonly, this is the dependence of pro-liferation on a particular hormone, or the the inhibition of growth by a mediator. Examples:   1.    Many breast cancers, like normal breast gland cells, are dependent on estrogens and / or gestagens for their growth. Receptor antagonists for estrogens (e.g., tamox-ifen) or gestagens (mifepristone, Figure 13.3) will there-fore stop or delay growth of these cells. Of course, these drugs will affect other hormone-dependent tissues as well – e.g., mifepristone will also disrupt the function of the plac...

  The cell cycle General cytotoxic drugs may be classified according to their relationship to the cell cycle (Figure 13.6). Cell cycle-spe-cific agents may affect either the S phase (i.e., DNA syn-thesis) or the M phase (i.e., mitosis). Cell cycle-nonselective agents may damage the cell throughout the cycle, mostly by direct chemical modification of the DNA.

  Alkylating agents Synthetic drugs that are not cell cycle-specific are mostly alkylating agents. They have diverse reactive groups. Sev-eral drugs share the `N-mustard' structure shown in Figure 13.7a. The reaction mechanism (formation of aziridine in-termediates that react as electrophiles; Figure 13.7b) is ac-tually the same as previously discussed for the irreversible  α -blocker phenoxybenzamine; here, however, we don't   have a moiety that targets the drug to any particular protein. It should go without saying that most molecules will actu-ally not react with DNA but instead with some other nucle-ophile hopping about in the cell, in particular glutathione or other sulfhydryls. However, those that do react with DNA are the ones that matter, since the harm done by them has the potential to be permanent. Also note that we have not one but two chloroethyl groups – this creates the possibili-ty of introducing cross-links into the DNA 7 . Cross-links be-tween the two str...

  Antibiotics Another class of DNA-damaging drugs are found in nature as antibiotics. Antibiotics are widely used by compet-ing soil microorganisms, both prokaryotic and eukaryotic. While many of them are selectively toxic for prokaryotic cells and therefore of use in antibacterial therapy, an even larger number is toxic for both prokaryotes and eukaryotes, often with higher toxicity for the latter. Several of these an-tibiotics have been useful in biochemical research because they can be used to dissect various stages of gene expres-sion and protein maturation.   The antibiotics used in cancer chemotherapy are most-ly DNA-intercalating agents. An example is provided by daunorubicin (Figure 13.10). This drug molecule has a large, flat polycyclic system, which will intercalate between the stacked base pairs of the DNA. However, there is more to it: The ring is also able to chelate iron, and the complex catalyses the formation of superoxide anions at the expense of glutathione (...

  Antimetabolites Cell cycle-selective agents comprise antimetabolites (of DNA synthesis) and inhibitors of mitosis (cell division; see below). A widely used example of an antimetabolite is 5-fluorouracil (5-FU; Figure 13.11). Before this drug ac-tually does something interesting, it needs to be converted to the nucleotide analog 5-fluoro-deoxyuridinemonophos-phate (5-FdUMP), which occurs in the same way as with normal uracil. 5-FdUMP is an analog of dUMP, which is the substrate for dTMP synthesis by thymidylate synthase; it is this reaction that is inhibited by dUMP (Figure 13.12a). The catalyt-ic mechanism of thymidylate synthase is depicted in Fig-ure 13.12b. The enzyme (thymidylate synthase) requires N,N'-methylene-tetrahydrofolic acid as a cosubstrate. The reaction is initiated by a cysteine residue in the active site of the enzyme and involves an intermediate in which the enzyme, the substrate (dUMP), and the cosubstrate are all covalently bound (bottom center in Figure 13.12...

Inhibitors of mitosis Inhibition of mitosis is caused by drugs that interfere with the polymerization of tubulin. The polymers of tubulin consist of  α , β  dimers, assembled in a helical fashion into a hollow fiber. These tubules are dynamically being formed and destroyed as needed by the cell; polymerization is GTP dependent. They are important in molecular transport and motion; broadly speaking, tubulin is to dynein what actin is to myosin. However, tubulin-dynein participates in other processes of molecular motion than actin/myosin, includ-ing the segregation of the chromosomes in mitosis. The mitotic spindle is the tubulin framework assembled for this purpose (Figure 13.15a). Formation of the spindle is inhib-ited by vincristine (Figure 13.15b). This drug molecule has a very nice complex structure, but I have not found any in-formation on how it actually fits to the target protein (tubu-lin). In any event, binding of vincristine still permits the tubulin dimer to associat...

  Monoclonal antibodies in tumour therapy While the picture given so far looks pretty bleak, there is hope of improvement. Among several new approaches to tumour therapy, monoclonal antibodies have started to make the most substantial contribution to improving its effectiveness and reducing the severity of side effects.   The use of antibodies is based on the fact that, due to al-tered gene expression patterns, many tumours possess one or more surface proteins that are not found on the healthy cells 14 . Antibodies that bind to cell surface antigens can in-duce cell destruction in various ways:   1.    By activating the complement system. This is a system of serum proteins that will bind to cell surface-bound antibodies and form holes in the cell membrane, thereby killing the cell. A straightforward example of this pro-cess is the destruction of blood cells by the transfusion of blood with incompatible blood type.   2.    By activating cytotoxic l...