Taxol (Paclitaxel) and Cancer Chemotherapy

2015

Taxol is an antineoplastic agent. This compound, first isolated from the bark of the Western yew tree in 1971, exhibits unique pharmacological actions as an inhibitor of mitosis, differing from the vinca alkaloids and colchicine derivatives in that it promotes rather than inhibits microtubule formation. Following its introduction into clinical trial, the drug was approved for treatment of cisplatin-refractory ovarian cancer in 1992 and has promising activity against cancers of the breast, lung, esophagus, and head and neck.

Malignant neoplastic diseases may be treated by various approaches: surgery, radiation therapy, immunotherapy, or chemotherapy, or a combination of these. The extent of a malignant disease (staging) should be ascertained in order to plan an effective therapeutic intervention. Plants have antineoplastic activities.

A significant portion of the product derived from plants serve either as protective agents against various pathogens (e.g., insects, fungi, or bacteria) or growth regulatory molecules (e.g., hormonelike substances that stimulate or inhibit cell division and morphogenesis).

Chemical Groups Of Natural Products With Anticancer Properties

Cancer Chemotherapy

Before discussing the specific pharmacokinetics and pharmacodynamics of each class of antineoplastic agent, several fundamental concepts and therapeutic objectives will be considered first.

Because a single cancerous cell is capable of multiplying rapidly and eventually causing the host’s death, one of the therapeutic objectives is to eradicate the last neoplastic cell. Unlike normal cells, cancerous cells multiply ceaselessly and, unless arrested, they will kill the host. In the early phase, cancerous cells grow exponentially. However, as the tumor grows in mass, the time needed for the number of cells to double also increases. The kinetics of cell multiplication are said to follow a Gompertzian growth curve. Tumor growth may be divided into three phases: (1) the subclinical phase, in which 10 x 104 cells are present, (2) the clinical phase, in which 10 x 108 cells (1-cm3 nodule) are present, and (3) the fatal phase, in which the number of cancerous cells equals or exceeds 10 x 1012.

Most human cancerous cells evolve from the single clone of a malignant cell. As a tumor grows, significant mutation takes place, producing cells that exhibit diversified morphological and biochemical characteristics.

During the subclinical phase, the rapidly growing cell population is uniform in character and thus highly sensitive to drug treatment; this is the reason for the importance of early diagnosis and treatment. During the clinical phase, the nondividing and slowly growing cells are nonuniform in character and less sensitive to drug treatment, thus necessitating the need for multiple-drug treatment.

Cell destruction with antineoplastic agents follows a first-order kinetic, indicating that the drugs kill a constant fraction of cells and not a constant number of cells.

Cytotoxic drugs are not specific in their actions. They arrest not only cancerous cells, but also normal cells, especially those of the rapidly proliferating tissues such as the bone marrow, lymphoid system, oral and gastrointestinal epithelium, skin and hair follicles, and germinal epithelium of the gonads. Consequently, the therapeutic regimen must be carried out using high-dose intermittent schedules and not a low-dose continuous approach. Succeeding doses are given as soon as the patient has recovered from the previous treatment.

Antineoplastic agents may be teratogenic, carcinogenic, or immunosuppressant, and they exert their lethal effects on different phases of cell cycle by being either cell-cycle specific or nonspecific.

The management of cancer includes treatment with alkylating agents (nitrogen mustards and alkyl sulfonates), antimetabolites (methotrexate and purine analogues), natural products (vinca alkaloids and taxol), miscellaneous compounds (hydroxyurea, procarbazine, and cis-platinum), hormones (estrogens and corticosteroids), and radioactive isotopes.

Alkylating Agents

Antimetabolites

Taxol and Cancer Chemotherapy: Natural Products

Miscellaneous Antineoplastic Agents

Asparaginase

Normal cells are able to synthesize asparagine but neoplastic tissues must obtain it from external sources. By metabolizing asparagine, asparaginase (Elspar) deprives the neoplastic tissues of asparagine, and in turn inhibits protein and nucleic acid synthesis. The resistant tumors are thought to possess higher than ordinary amounts of asparagine synthetase. Asparaginase, which is prepared from Escherichia coli, is used to induce remission of acute lymphocytic leukemia. Asparaginase causes malaise, anorexia, chills, fever, and hypersensitivity reactions. In general, it does not damage the bone marrow or other rapidly growing tissues as much as other antineoplastic agents do.

Hydroxyurea

Hydroxyurea suppresses DNA synthesis by inhibiting ribonucleoside diphosphate reductase, which catalyzes the reduction of ribonucleotides to deoxyribonucleotides. Hydroxyurea is used in chronic cases of granulocytic leukemia that are unresponsive to busulfan. In addition, it is used for acute lymphoblastic leukemia. Hydroxyurea may cause bone marrow depression.

Cis-Platinum

Cis-platinum (cisplatin) binds to intracellular DNA, causing both interstrand and intrastrand cross-linking. It is a cell-cycle phase nonspecific agent. Cis-platinum, which is ineffective orally, is used for testicular, bladder, and head and neck cancers. It precipitates nephrotoxicity, ototoxicity, and gastrointestinal injury.

Carboplatin

Carboplatin is a promising second-generation platinum agent. Because it is less reactive, it causes less nephrotoxicity, myelosuppression, and thrombocytopenia.

Procarbazine

Procarbazine (Matulane) inhibits DNA, RNA, and protein synthesis through the operation of an unknown mechanism. It is effective in patients with Hodgkin’s disease when given in combination with mechlorethamine, vincristine, and prednisone (MOPP). Procarbazine causes neurotoxicity, bone marrow depression, and gastrointestinal injury.

Etoposide

Etoposide is used to combat several types of tumors, including testicular and small-cell lung cancers, lymphoma, leukemia, and Kaposi’s sarcoma.

Cancer Chemotherapy-Induced Emesis

Nausea and vomiting are frequent side effects of radiotherapy and cancer chemotherapy. The incidence of this is relatively low for bleomycin, vincristine, and chlorambucil but is high for the remaining agents. Besides prochlorperazine and metoclopramide (dopamine receptor-blocking agents), nabilone (a cannabinoid), batanopride, granisetron, and ondansetron (all serotonin receptor-blocking agents) have been shown to be effective in ameliorating these symptoms.