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Chapter: Biochemical Pharmacology : Some principles of cancer pharmacotherapy

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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.

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 placenta in pregnancy, and in fact is used more com-monly for abortion than for cancer treatment.

 

2.  Hairy-cell leukemia is a rare form of lymphatic4 leukemia. Proliferation of the malignant cells is very ef-ficiently inhibited by interferon- α. This is one of the few cases so far in which a `biological' therapy has actually lived up to its promise.

 

3.  Promyelocytic leukemia is caused by a very specific ge-netic event – the reciprocal translocation of some seg-ments between chromosomes 15 and 17 (Figure 13.4).

 

The `rift' of translocation goes right through the gene for α-retinoic acid receptor, which therefore is ex-pressed in two deviant forms. Retinoic acid, via its re-ceptors, acts as a transcriptional regulator in the final differentiation of the promyelocytes to granulocytes. This differentiation is arrested by the functionally de-viant receptors. Promyelocytes proliferate, while granu-locytes don't; arrest of differentiation therefore leads to the build-up of a proliferating yet useless (even harm-ful) cell population. However, it is possible to restore differentiation to the aberrant cells by the application of retinoic acid in larger than physiological amounts. This is probably due to the fact that the cells are diploid, and the second set of chromosomes 15 and 17 is intact, thus providing for an intact copy of the α-retinoic receptor gene5.

 

4.  Another example of cell type-specific chemotherapy is the use of mitotane (Figure 13.5) in adrenal gland can-cer (those derived from the cortex, not the medulla of the adrenal gland). Selective toxicity is conferred by the enzyme 11-β-hydroxylase, a member of the cytochrome P450 family that is located in the mitochondria of the adrenal gland cortical cells and participates in the synthesis of glucocorticoids (e.g., cortisone). Mitotane is a substrate6 for this enzyme, which converts it to an acyl chloride. The acyl chloride in turn reacts with sever-al proteins in the mitochondria, which will irreversibly damage the cells.

 

Importantly, with all of the above cell-specific therapies, resistance is common, either primarily (no response to be-gin with) or secondarily (initial response but emergence of non-responsive cell clones). These therapies therefore typically have to be combined or followed up with one of the general, non-cell-specific cytotoxic therapies described below.


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