Tumour sensitive

Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G Marciano R, Ciardiello F, Tortora G. (2008) Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer 98 923-930. 

Edelstein MB, Smink T, Ruiter DJ, Visser W, van Putten LM. Improvements and limitations of the sub-renal capsule assay for determining tumour sensitivity to cytostatic drugs. Eur J Cancer Clin Oncol 1984 20 1549-56. 

Like the triazenes, the nitrosoureas show many points of resemblance to the difunctional alkylating agents. They inhibit a range of animal tumours sensitive to alkylating agents, but not a hamster tumour with acquired resis-... 

On the present evidence it cannot be unequivocally stated that DNA is the only target site of importance for the alkylating agent, but cross-linking of molecules obviously plays an important part in their cytotoxic action. Many of their effects can be related to interference with normal DNA function, but no correlation has been shown in whole animals between alkylation of DNA and tumour sensitivity. Tumours differing as much as one hundredfold in their sensitivity to alkylating agents may have equal levels of DNA alkylation. 

Decreased activity of the thyroid gland results in hypothyroidism and, in severe cases, myxoedema. It is often of immunological origin and the manifestations are low metabolic rate, slow speech, lethargy, bradycardia, increased sensitivity to cold, and mental impairment. Myxoedema includes a characteristic thickening of the skin. Therapy of thyroid tumours is another cause of hypothyroidism. Thyroid deficiency... 

Optical activity in metal complexes may also arise either if one of the ligands bound to the metal in the first co-ordination sphere is itself optically active or if the complex as a whole lacks a centre of inversion and a plane of symmetry. Thus all octahedral cts-complexes of the tris-or bis-chelate type have two isomeric forms related by a mirror plane, the d- and /-forms. These species have circular dichroism spectra of identical intensities but opposite in sign. The bands in the circular dichroism spectrum are, of course, modified if ligand exchange occurs but they are also exceedingly sensitive to the environment beyond the first co-ordination sphere. This effect has been used to obtain association constants for ion-pair formation. There also exists the possibility that, if such compounds display anti-tumour activity, only one of the mirror isomers will be effective. 

Rhodes A, Jasani B, Anderson E, et al. Evaluation of HER-2/neu immunohisto-chemical assay sensitivity and scoring on formalin fixed and paraffin processed cell lines and breast tumours. Am. J. Clin. Pathol. 2002 118 408-417. 

TNF fails to induce death of all tumour cell types. Although many transformed cells are TNF sensitive, the cytokine exerts, at best, a cytostatic effect on others and has no effect on yet others. The cytotoxic activity is invariably enhanced by the presence of IFN-y. The concurrent presence of this interferon increases the range of transformed cell types sensitive to TNF-a, and can upgrade its cytostatic effects to cytotoxic effects. It can also render many untransformed cells, in particular epithelial and endothelial cells, susceptible to the cytotoxic effects of TNF-a. 

Yet another strategy that may prove useful is the introduction into tumour cells of a sensitivity gene. This concept dictates that the gene product should harbour the ability to convert a non-toxic pro-drug into a toxic substance within the cells - thus leading to their selective destruction. The model system most used to appraise such an approach entails the use of the thymidine kinase gene of the herpes simplex virus (Figure 14.12). 

The pH determination by 31P NMR spectroscopy mainly reflects intracellular pH, as the phosphorus compounds and metabolites essentially are located in the intra-cellular space.223 However, NMR spectroscopy also provides possibilities for measuring extra-cellular pH using a pH-sensitive probe that remains extra-cellular. This has for example been demonstrated by Ojugo et al.,224 who used the 31P probe 3-aminopropyl phosphonate and the 19F probe 3-[/V-(4-fluoro-2-triflourmethylphenyl)-sulphamoyl]-propionic acid to determine extra-cellular pH in tumours. 

Andrieu-Abadie, N., Carpentier, S., Salvayre, R., and Levade.T., 1998, The tumour necrosis factor-sensitive pool of sphingomyehn is resynthesized in a distinct compartment of the plasma membrane. Biochem J. 333 91-97. 

Drugs that can be used to control tumour cell proliferation inhibit a variety of enzymes, including thymidylate synthase and topoisomerase (Chapter 20). The enzyme aromatase converts a ring in a steroid to an aromatic ring. It converts, for example, adrenal steroid hormones into female sex hormones, which bind to oestrogenic receptors in the ovary or breast and increase the risk of ovarian or breast cancer. Aromatase inhibitors are used to treat patients with breast or ovarian cancers that are sensitive to oestrogen. Unfortunately, none of the inhibitors is specific for enzymes in tumour cells and they can therefore have severe side-effects (Chapter 21). 

Polymeric micelles are mostly small (10-100 nm) in size and dmgs can be incorporated by chemical conjugation or physical entrapment. For efficient delivery activity, they shonld maintain their integrity for a sufficient amount of time after injection into the body. Most of the experience with polymeric micelles has been obtained in the field of passive targeting of anticancer drugs to tumours [33]. Attachment of antibodies or sugars, or introduction of a polymer sensitive to variation in temperature or pH has also been stndied [32]. 

Non-surgical methods of cancer treatment, primarily radiation therapy and chemotherapy, rely almost exclusively on procedures that kill cells. The main problem with these treatments is that they do not provide specificity for cancer cells. In the case of radiation therapy, a degree of specificity is achieved by localizing the radiation to the tumour and its immediate surrounding normal tissue. For anti-cancer drugs, it is primarily the rapid proliferation of many of the cancer cells that makes them more sensitive to cell killing than their normal counterparts. However, both modalities are limited by their cytotoxic effects on normal cells. In the case of radiotherapy, normal tissue surrounding the tumour limits the radiation dose, where-... 

Although tumour growth inhibition by 6-mercaptopurine has been attributed to the inhibition of the conversion of inosinic acid to adenylic acid [309, 310, 312], probably at the first step, this conversion by cell-free extracts from the exquisitely sensitive tumour adenocarcinoma 755 was inhibited only at high levels of 6-mercaptopurine ribonucleotide [313]. Furthermore, hadacidin (A -formylhydroxyaminoacetic acid) is an excellent inhibitor of adenylosuccinate synthetase [314, 315], and yet it has little antitumour activity and is not cytotoxic, showing that this inhibition may be relatively unimportant to cells. 

The reason for the selective toxicity of 6-mercaptopuiine remains to be established, but two factors may be of primary importance. 6-Mercaptopurine is anabolized primarily, if not exclusively, to the monophosphate level, and it is readily catabolized by xanthine oxidase, an enzyme that is low in most cancer cells compared to normal cells. Another factor that must be considered is the metabolic state of the target cells. Actively proliferating leukaemia cells are more sensitive to 6-mercaptopurine, as they are to all antimetabolites, than cells in the so-called Gq or stationary phase. Although this does not explain the difference between 6-mercaptopurine and other purine analogues, it may explain the ineffectiveness of 6-mercaptopurine against solid tumours, most of the cells of which are in the non-dividing state. 

Statistically, oncogenicity studies have a low sensitivity because of the small numbers of animals that are used. However, complex statistical analysis, which should include a judgement on whether the tumour was the cause of death, duration to death and trend analysis can reveal valuable information about the risk to man of taking the product therapeutically. 

Another interesting development is the use of the naturally occurring herbal extract hypericin (4.35), which has the extended quinone structure (4.35), in both photodiagnosis and therapy. This is given to the patient, either orally or topically, who is then illuminated with blue hght. The cancer tumours show up as red spots, the hght from which can be recorded on a red sensitive camera, subjected to computational analysis and then converted into an image on the computer. 

A formal comparison of the two treatments could be based on the unpaired t-test, comparing the mean time to disease recurrence in the test treatment group with the mean time to disease recurrence in the control group. While this is a valid test, it may not be particularly sensitive. The separation between the two groups is clear, but if we now simply read off the times to disease recurrence on the y-axis we will see considerable overlap between the groups we will have lost some sensitivity by ignoring the size of the primary tumour variable. 

This technique is called analysis of covariance (ANCOVA) and size of the primary tumour is termed the covariate. Taking account of the covariate here has led to a much more powerful analysis than that provided by the simple unpaired t-test. Of course the main reason why we are seeing such an improvement in sensitivity is that the covariate is such a strong predictor of outcome. These improvements will not be quite so great with weaker predictors. 

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