Chemotherapy, cytotoxic

A. Bielawska, K. Bielawski, K. Chrzanowski, S. Wolczynski, Prolinase-Activated Prodrug for Cancer Chemotherapy. Cytotoxic Activity of Proline Analogue of Chlorambucil in Breast Cancer MCF-7 Cells , Farmaco 2000, 55, 736-741. 

Bielawska, A., Bielawska, K., Chrzanowski, K., and Wolczynski, S. Prolidase-activated prodrug for cancer chemotherapy cytotoxic activity of praline analogue of chlorambucil in breast cancer MCF-7 cells. II Farmaco 55 736-741, 2000. 

Clinically, GM-CSF or G-CSF have been used to accelerate recovery after chemotherapy and total body or extended field irradiation, situations that cause neutropenia and decreased platelets, and possibly lead to fatal septic infection or diffuse hemorrhage, respectively. G-CSF and GM-CSF reproducibly decrease the period of granulocytopenia, the number of infectious episodes, and the length of hospitalization in such patients (152), although it is not clear that dose escalation of the cytotoxic agent and increased cure rate can be rehably achieved. One aspect of the effects of G-CSF and GM-CSF is that these agents can activate mature cells to function more efficiently. This may, however, also lead to the production of cytokines, such as TNF- a, that have some toxic side effects. In general, both cytokines are reasonably well tolerated. The side effect profile of G-CSF is more favorable than that of GM-CSF. Medullary bone pain is the only common toxicity. 

CarbocycHc 2/3 -didehydro-2/3 -dideoxyguanosine [118353-05-2] (carbovk, CBV, 66), C H 2N502, synthesized in 1988 (177), is a promising candidate for the chemotherapy of AIDS. CBV inhibits HIV repHcation and HIV-induced cytopathic effects in a variety of human T-lymphoblastoid ceU lines at concentrations approximately two hundred- to four hundredfold below its cytotoxic concentrations (177). CBV is as effective as AZT and DDC in reducing the expression of vkal antigen in HIV-infected CEM ceUs (177). The antivkal potency and selectivity of carbovk is comparable to the anti-HIV-1 potency and selectivity of 2/3 -dideoxyadenosine (178). The exact mode of antivkal action of carbovk has not yet been elucidated, but may be the modulating effect of intraceUular nucleotides on 5 -nucleotidase activity (179). 

Approaches to cytotoxic chemotherapy iaclude special emphasis on dmg targeting and toxicity alleviation. The directions ia which new dmg discovery strategies are moving and the criteria used for advanciag compounds iato clinical trials (2) are discussed hereia, as are all of the dmgs approved by the United States Food and Dmg Administration (FDA) for the treatment of cancer as of this writing and those compounds ia clinical trials. 

Patients receiving cytotoxic chemotherapy very often need concomitant administrating of antiemetic therapy. Such protocols will start well in advance of administering the cytotoxic, and last for a reasonable time with regard to pharmacokinetics of the antineoplastic agent. In addition, side effects of antineoplastic therapy are made better tolerable by supportive care. 

Cytotoxics also cause cellular damage and the release of serotonin and other mediators from enterochromaffin cells. There is conflicting evidence regarding whether 5-HT3 receptors in the medulla are activated also during chemotherapy and contribute to production of emesis. Currently, the weight of evidence favours peripheral 5-HT3 receptors, with minor involvement of central receptors. 

Nicotinamide potentiates the cytotoxic effects of chemotherapy and radiation treatment against tumor cells. This effect is probably attributable to increased... 

The nitrogen mustards are cytotoxic chemotherapy agents which are chemically derived from mustard gas. Although their current use is medicinal, the predecessor of these compounds was also used for chemical warfare putposes. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

TNF was originally identified because of its cytotoxic activity against some tumor cell lines and its ability to induce hemorrhagic necrosis of solid tumors in various animal models. However, the clinical use of TNF as an anticancer drug has been so far limited by its severe cardiovascular side effects. Therefore, TNF treatment is limited to regional and local administration of high doses of TNF, often in combination with chemotherapy, as accomplished in isolated limb and isolated hepatic perfusion (ILP and IHP, respectively) [5]. In the case of ILP, typically metastases are treated, patients benefit from this procedure by salvage of limbs from a loss by amputation. 

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. 

Cytotoxic chemotherapy is eventually required in most patients with metastatic breast cancer. Patients with hormone-receptor-negative tumors require chemotherapy as initial therapy of symptomatic metastases. Patients who respond initially to hormonal manipulations eventually cease to respond and go on to require chemotherapy. The median duration of response is 5 to 12 months, but some patients will have an excellent response to an initial course of chemotherapy and may live 5 to 10 years or longer without evidence of disease. In general, median survival of patients after treatment with commonly used drug combinations for metastatic breast cancer is 14 to 33 months. The median time to response has ranged from 2 to 3 months in most studies, but this period depends in large part on the site of measurable disease. The median time to appearance of response is between 3 and 6 weeks in patients whose disease is primarily in the skin and lymph nodes, 6 to 9 weeks in patients with metastatic lung involvement, 15 weeks in patients with hepatic involvement, and nearly 18 weeks in patients with bone involvement. Thus it is often the case that an immediate response to therapy is not... 

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