Cytostatic chemotherapy

Fig. 8.2 Pronounced, toxic fatty liver following cytostatic chemotherapy with recorded values of between —9.9 and -1.1 HU. The liver is homogeneously dark (compared to the bright spleen). The vessels appear brighter (values of between +40 and +50 HU)...

Severe allergic reactions can occnr to parenterally administered lipid solutions. Such reactions may be mistaken for symptoms of the underlying disease or adverse effects of cytostatic chemotherapy (123). There is some evidence that the presence of soya bean proteins is responsible. 

Of 535 patients who received thahdomide with or without cytostatic chemotherapy, 82 developed a deep venous thrombosis (31). Multivariate analysis showed that the combination of thahdomide with chemotherapy that contained doxorubicin was associated with the highest odds ratio (OR = 4.3). Newly diagnosed disease (OR = 2.5) and chromosome 11 abnormahties (OR = 1.8) were also... 

There are cases when heavy metals are used in chemotherapy, for example cytostatic chemotherapy with as-platinum (Rosenberg 1969 [cited by Lippert 1999], Garban etal. 1989, Haiduc and Silvestru 1989, Johnsson et al. 1995). Numerous research studies into the interaction of DNA with metal ions also dealt with ds-platinum (Lippert 1999, Garban 2000). Cis-platinum interacts with nucleosides preferentially through the Ny site of guanine, but may also form bidentate chelates as a result of interaction both with Ny and sites. Modifications induced to ds-platinum by the interaction with guanine have been studied using quantum chemistry (Lippert 1999, Chojnacki et al. 2001). 

Treatment for tumor patients with synthetic drags -chemotherapeutics - that may be of completely different chemical structure. The main goal of tumor chemotherapy is to achieve a selective toxicity for the tumor without causing damage to the host, for instance by combining several cytostatic drags at doses lower than required for monotherapy. 

A frequently used procedure is targeted irradiation with y-rays, which block cell reproduction due their mutagenic effect (see p. 256). Another approach is to inhibit cell growth by chemotherapy. The growth-inhibiting substances used are known as cytostatic drugs. Unfortunately, neither radiotherapy nor chemotherapy act selectively—i. e., they damage normal cells as well, and are therefore often associated with severe side effects. 

As described above, cancer cells produce or induce other cells to produce hyalurooan. This halo of hyaluronan protects the cells against macrophages or leukocytes and shields them from cytostatics. Several studies have dealt with the addition of hyaluronidase to chemotherapy in order to degrade the hyaluronan coaling and to render the cells more accessible to the cytostatic drugs. 

Recently, it was shown that various nitrogen mustard-based cytostatics, for example, melphalan and cyclophosphamide, reacted with the cysteine 34 residue of human serum albumin in an analogous way. The tripeptide assay could be applied to samples of cancer patients treated with these cytostatics (28), which holds promise for optimization of chemotherapy with these agents by intensive screening of adduct levels in patients. 

Skipper-Schobel-Wilcox model is based on two important presumptions exponential growth and homogeneous sensitivity to chemotherapy. Model should not "work" effectively if some cells in tumor are biochemically refractorious to applied dozes of cytostatic agents. If such cells exist, then even in the case of elimination of all sensitive cells by definite duration of medical treatment the further therapy by the same scheme wouldn t help. 

That is why the best strategy of cancer chemotherapy is medical treatment at minimum tumor size before the cells will acquire resistance and ability to metastasis. Correspondingly, if the treatment was started then maximum number of effective preparations should be applied as soon as possible. The main problem at that is prevention of development of cells resistance to a lot of cytostatic agents in the case of acquiring of such ability in relation to one of them. This recommendation corresponds to principles underlying combined chemotherapy. 

Lipiodol (= iodized ester of poppyseed oil) used as a contrast medium for lymphography accumulates selectively in the tumour over a longer period of time. As a result, local-interventional (oily) lipiodol chemotherapy (TOCE) was developed. Lipiodol acts as a carrier for the admixed cytostatic agents, so that the latter retain their effect in the tumour long-term in a high (systematically unacceptable) dose. Hereby, cisplatin or epidox-orubicin (101) is emulgated in lipiodol. It was possible to achieve 1-year survival rates of 36-55%. Other cytostatics did not prove to be any more effective. 

To date, chemotherapy for CCC has remained unsuccessful, no matter what kind of substance is used in monotherapy or polytherapy (e.g. 5-FU plus leuco-verin). Local chemotherapy using arterial infusion of cytostatics may be indicated in individual cases. Radiotherapy has no influence on survival time, but usually reduces pain. 

Systemic chemotherapy is usually not indicated in non-colorectal liver metastases due to lack of response. The systemic administration of cytostatics (also in combination) possesses the status of palliative therapy. However, in metastatic neuroendocrine tumours, a combination of octreotide -i- IFN had a positive effect on the survival time. Systemic chemotherapy produced remission rates of up to 60%. (320) In metastatic breast cancer, systemic chemotherapy is indicated, usually in combination with hormonal and immune therapy. (316, 342) In metastatic gastric carcinoma, palliative chemotherapy can achieve a remission rate of up to 40%, with a slight extension of survival time. 

In 43 patients, raised plasma concentrations of FLT3-L (an fms-like tyrosine kinase) in patients who had previously received chemotherapy predicted the stage of recovery of the bone-marrow compartment (40). FLT3-L seems to identify the hkelihood that the patient will have severe thrombocytopenia if additional cytostatic therapy is given. Knowledge of bone-marrow activity... 

Nausea and vomiting are common adverse effects of cytostatic drugs (48). They can be acute (occurring within 24 hours of therapy), delayed (persisting for 6-7 days after therapy), or anticipatory (occurring before chemotherapy) (49). Their treatment has been reviewed (50,51). 

In a retrospective analysis over 13 years of cytostatic therapy for various conditions there were 12 cases in which chemotherapy had caused gastrointestinal perforation (43). Six doses of etoposide each of 250 mg/m induced an advanced stage (grade 4) of mucositis. Fifty percent of patients receiving epirubicin 120 mg/m ... 

Why then, since such an abundance of metabolic inhibitors is available, do so few of them find practical application Examples are the folic acid reductase inhibitors, such as aminopterin, the purine and pyrimidine analogs used as cytostatics in cancer chemotherapy and known for their high toxicity in a wide variety of species, and the organic phosphates and carbamates used as insecticides but also highly toxic to mammals. Lack of selectivity in the action of metabolic inhibitors is inherent in their mechanism of action due to the universality of biochemical processes and principles throughout nature. Selectivity in action requires species differences in biochemistry. For the antivitamins, for instance, there is not only a lack of species differences in action in addition, the fact that vitamins often serve as cofactors for a variety of enzymes is a serious drawback to endeavors to obtain agents with species-selective action. 

As already seen in the previous section, the efficiency of chemotherapy is often decreased by the development of resistance of cancer cells to the cytostatic drugs (MDR). Since it has been shown that, generally, the phenothiazines have the effect of diminishing the MDR and increasing the cytostatic efficiency, it seemed worthwhile to examine whether the benzo[a]phenothiazines presented the same type of properties. 

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