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
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
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
Cumulative injury to the bone marrow from alkylating agents, such as
nitrosoureas and 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
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).[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, trimetrexate (Neutrexin),
fluorouracil, and 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 induce changes characteristic
of apoptosis in chronic myelogenous leukemia. DNA topoisomerase I and
II inhibitors, cytarabine, and paclitaxel (Taxol) also trigger changes
characteristic of apoptosis in various types of leukemia. 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, 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
(Cytoxan, Neosar) and ifosfamide (Ifex), probably result from the renal
excretion of highly reactive, aquated platinum species and toxic metabolites,
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 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.
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