New regimens of cancer chemotherapy combine drugs that have the potential to produce additive or synergistic antitumor effects without treatment-limiting overlapping toxicities. These regimens have been designed to maximize antitumor effects while maintaining an acceptable safety profile. Although this approach has achieved long-term disease-free survival in many children with malignant tumors and in adults with leukemia, lymphoma, and germ-cell neoplasms, success has been limited in the epithelial tumors more commonly seen in adult patients.
Extended analysis of clinical trials of chemotherapy with and without radiation therapy in patients with a variety of relatively responsive neoplasms, including lymphoma, germ-cell tumors, and ovarian and breast cancer, has revealed that administration of a high percentage of the planned treatment dose according to the planned schedule produces an improved response rate and duration of response.[1-3] As a result, there is great interest in developing supportive therapy that will permit a higher percentage of patients to receive their planned therapy or even to permit the administration of a higher cumulative dose or greater dose intensity so as to achieve improved response rates and survival duration.
The development and potential application of agents that can reduce toxicity to normal tissues but not to malignant cells are the subject of intense investigation. Two different approaches are actively undergoing evaluation: (1) administration of cytoprotective agents before chemotherapy or irradiation, and (2) administration of rescue agents, such as bone marrow colony-stimulating factors (CSFs), after therapy. This review will explore the differences between these two approaches (ie, protection vs rescue), their advantages and limitations, and the possibility of their complementary use.
Chemotherapy may produce toxicity in a broad range of normal tissues and organs. The bone marrow, gastrointestinal (GI) epithelium (including the oral mucosa), kidney and urinary bladder, peripheral nerves, central nervous system, and heart and lungs have proved to be of primary concern with regard to dose-limiting toxicity. Acute drug effects on the bone marrow and gut typically determine the timing of repeated courses or cycles of treatment.
Cumulative injury to the bone marrow from alkylating agents, such as nitrosoureas and mitomycin(Drug information on mitomycin) (Mutamycin), or parenchymal toxicities , such as nephrotoxicity, peripheral neuropathy, and ototoxicity (cisplatin [Platinol]), cardiotoxicity (anthracyclines), lung and vascular endothelial cell toxicity (bleomycin [Blenoxane]), and lung and kidney toxicity (mitomycin) affect the ability to deliver the full, scheduled course of therapy without producing persistent or irreversible toxicity. In combined-modality regimens, cardio-pulmonary and mucosal toxicities are further exacerbated when the affected organs are within the radiation field.
In oncologic practice, cumulative toxicities are minimized by setting an upper limit for the total cumulative dose and by controlling individual doses, dosing frequency, and concomitant therapies. It is in this context that a broadly applicable cytoprotectant would be of great value if it could selectively protect normal organs but not the neoplastic cells.
Cytotoxic Mechanisms of Anticancer Treatments
Anticancer agents exert their therapeutic benefits by inducing cytotoxic effects or initiating apoptosis (programmed cell death) in neoplastic cells (Table 1).
Cytotoxicity results from the action of chemotherapeutic agents that undergo chemically or enzymatically induced transformation to highly reactive species. These species, in turn, react with DNA (alkylating agents, organoplatinum compounds) or generate superoxide or hydroxyl free radicals, which are damaging to DNA, cellular lipids, and cell membranes (anthracyclines, bleomycin(Drug information on bleomycin)).[4,5] In addition, some agents interfere with the biochemical processes that regulate normal cellular activity. Vinca alkaloids and taxanes prevent microtubule formation and dissolution, respectively, disrupting cytoskeletal integrity. Antimetabolites, such as methotrexate(Drug information on methotrexate), trimetrexate (Neutrexin), fluorouracil(Drug information on fluorouracil), and cytarabine(Drug information on cytarabine), interfere with the synthesis of DNA.
Dysregulation of apoptosis is now regarded as an important factor in the development of carcinogenesis. Some investigations suggest that tumor growth is more a function of reduced rates of cell death than of enhanced proliferation. Repressed apoptosis has been attributed to a mutation of the tumor-suppressor protein p53,[7,8] overexpression of the bcl-2 apoptosis- inhibitor gene,[9-11] or alteration in the expression of other apoptosis-related proteins or oncogenes, such as c-myc, APO-1, Fas, and BAX.
Chemotherapeutic agents can facilitate apoptosis under certain conditions. For instance, hydroxyurea (Hydrea) and doxorubicin(Drug information on doxorubicin) induce changes characteristic of apoptosis in chronic myelogenous leukemia. DNA topoisomerase I and II inhibitors, cytarabine, and paclitaxel(Drug information on paclitaxel) (Taxol) also trigger changes characteristic of apoptosis in various types of leukemia. Tamoxifen(Drug information on tamoxifen) (Nolvadex), an antiestrogen, induces morphologic and biochemical changes typical of apoptosis in human breast cancer cells,[17,18] and 4-hydroperoxycyclophosphamide (perfos-famide [Pergamid]), cisplatin(Drug information on cisplatin), and paclitaxel also cause apoptosis-related changes in ovarian cancer cell lines with p53 mutants.
The physiologic manifestations of cytotoxicity relate to the cytotoxic mechanisms of the various chemotherapeutic agents used. Bleomycin damages the lung by injuring alveolar cells and vascular endothelial cells via oxygen radical species. Anthracycline cardiotoxicity results from free-radical injury produced by a drug-iron conjugate. Cisplatin nephrotoxicity and the urotoxic effects of alkylating agents, such as cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) and ifosfamide(Drug information on ifosfamide) (Ifex), probably result from the renal excretion of highly reactive, aquated platinum species and toxic metabolites, respectively.
Strategies to overcome unwanted cytotoxic effects have been developed from our understanding of the mechanism of action of anticancer agents. For example, elucidation of the enzymatic inhibitory effect of methotrexate and trimetrexate(Drug information on trimetrexate) permitted identification of leucovorin as a rescue agent to bypass the enzymatic blockade.
All current active cancer treatments produce injury to both neoplastic and normal cell populations. Cytoprotective strategies attempt to protect normal cells and tissues from injury without protecting cancer cells. Cytoprotective agents are administered before the anticancer therapy. In contrast, cytokine rescue strategies do not protect normal cells, but rather, attempt to accelerate the production of hematologic elements from surviving stem cells to replace those killed or damaged during chemotherapy. Cytokines are administered after cytotoxic therapy in order to prevent accentuated toxicity to stem cells forced into DNA synthesis while being exposed to chemotherapy.