Cytotoxic drugs chemotherapy

To translate this approach into clinical scenarios, the risk-benefit assessment of chemotherapy administration in already immunocompromised patients would favor situations in which cytotoxic drugs are indicated anyhow, such as in AIDS-related lymphomas, where alkylating agents are part of the standard regimens. 

Since the late 1940s, when Farber treated leukemia with methotrexate, cancer therapy with cytotoxic drugs made enormous progress. Chemotherapy is usually integrated with other treatments such as surgery, radiotherapy, and immunotherapy, and it is clear that postsurgery, it is effective with solid tumors. This is due to the fact that only systemic therapy can attack micrometastases. 

Multidrug resistance (MDR) is the name ascribed to the phenomenon whereby cancer cells and tumors develop resistance to chemotherapeutic agents. Conceptually, this can be viewed as a survival response whereby cancer cells endeavor to ward off cytotoxic compounds. Mechanistically, MDR is typically mediated by overexpression of P-glycoprotein (P-gp aka ABCB1) or other plasma membrane ATPases that export cytotoxic drugs used in chemotherapy, thereby reducing their efficacy. 

Cyclopamine also interferes with cholesterol metabolism that results in decreased cholesterol synthesis and the accumulation of late biosynthetic intermediates. Cyclopamine was evaluated as an inhibitor of multi-drug resistance in tumor cells. Intrinsic or acquired resistance of tumor cells to cytotoxic drugs is a major cause of failure of chemotherapy. Both cyclopamine and the spirosolane alkaloid tomatidine from tomatoes act as potent and elfective chemosensitizers in multidrug-resistant cells (Lavie et ah, 2001). Therefore, plant steroidal alkaloids, such as cyclopamine and tomatidine, or their analogs, may serve as chemosensitizers in combination with chemotherapy and conventional cytotoxic drugs for treating multidrug-resistant cancers. 

Neutropenia is a common adverse effect of the cytotoxic drugs used to treat cancer and increases the risk of serious infection in patients receiving chemotherapy. Unlike the treatment of anemia and thrombocytopenia, transfusion of neutropenic patients with granulocytes collected from donors is performed rarely and with limited success. The introduction of G-CSF in 1991 represented a milestone in the treatment of chemotherapy-induced neutropenia. This growth factor dramatically accelerates the rate of neutrophil recovery after dose-intensive myelosuppressive chemotherapy (Figure 33-5). It reduces the duration of neutropenia and usually raises the nadir count, the lowest neutrophil count seen following a cycle of chemotherapy. 

A major cause of morbidity and mortality in patients who receive cytotoxic treatment or radiotherapy for cancer is bacterial and fungal infections. Intensive chemotherapy is associated with fever and infection, and the development of neutropenia further increases this risk of infection. Consequently, maximum doses of some cytotoxic drugs are limited due to bone marrow toxicity. Higher doses of chemotherapy and radiation therapy have become possible due to a reduction in bone marrow damage with the availability of the CSFs for clinical use. 

Drugs used in cancer chemotherapy are cytotoxic drugs, hormones, plant derivatives, radioactive isotopes, and miscellaneous agents (e.g., procarbazine, hydroxyurea, mitotane). The plant-based drugs vincristine, vinblastine, vinorel-bine, etoposide, and campothecins. Radioactive isotopes, such as 131 iodine (131 I), are used in the treatment of thyroid tumors. Cytotoxic drugs (e.g., cis-platin, cyclophosphamide, 6-mercaptopurine, 5-fluorouracil, and methotrexate are used for the treatment of cancer. 

The treatment of choice for leukemia is chemotherapy, but because of the blood-brain barrier cytotoxic drugs are ineffective in treating leukemic optic neuropathy. Radiotherapy is the preferred treatment for the optic neittopathy because the optic nerve is relatively insensitive to radiotherapy but the leukemic cells are very radiosensitive. Chemotherapy and local irradiation have not shown promise in the treatment of lymphomatous optic neittopathy Meningiomas, likewise, are insensitive to chemotherapy and irradiation and require surgical excision. 

Radiation recall consists of inflammatory reactions triggered by cytotoxic drugs in previously irradiated areas most are skin reactions. Gemcitabine has been implicated in several cases. The authors of a literature review discovered 12 cases of radiation recall caused by gemcitabine and reported a case of myositis in the rectus abdominis muscle of a patient with pancreatic adenocarcinoma as an effect of radiation recall (23). Most of the cases had inflammation of internal organs or tissues and 30% had dermatitis or mucositis. This is different from the effect of other agents that commonly cause radiation recall (anthracyclines and taxanes), with which 63% are skin reactions. Compared with anthracyclines and taxanes, the interval from the completion of radiation therapy to the start of chemotherapy is less with gemcitabine (median time 56 days, compared with 218 days for the taxanes and 646 days for doxorubicin). 

Whatever the truth of the matter, G-CSF should be regarded as a possible cause of pulmonary complications. The abrupt increase in the number of activated neutrophils after G-CSF may account for exacerbation of latent chemotherapy-induced pulmonary damage. Endothelial damage subsequent to increased neutrophil activity (that is, enhanced superoxide release and increased adhesion molecule expression and adherence) or the release of cytokines (IL-1, IL-6, TNF) has been advanced as possible mechanisms. In addition, transient slight hypoxia was found in G-CSF users, although no relation with specific cytotoxic drug treatment or previous radiotherapy was identified (32). A sudden increase in neutrophil count, a rise in LDH and C reactive protein, and the occurrence of dyspnea or fever in G-CSF-treated patients were proposed as possible early signs of the subsequent development of interstitial pneumonia. 

A series of examples reveal that cell systems like these can be used in wide ranging studies of, for example, cancer sensitivity to radiation and chemotherapy and the analysis of penetration by cytotoxic drugs in targeted tumour therapies... 

Rapidly proliferating normal cells are more sensitive to cytotoxic drugs. Bone marrow suppression [ often determines the upper limit of tolerable chemotherapy. Table Vll-l-l lists mechanisms of action, selected clinical uses, and adverse effects of major anticancer drugs. Table VIII-l-2 shows the dose- j limiting and distinctive toxidties of anticancer drugs. j... 

---