Taxol and Cancer Chemotherapy: Natural Products

2015

Vinca Alkaloids

The vinca alkaloids (vinblastine, vincristine, and vindesine), which bind to tubulin, block mitosis with metaphase arrest. Vinca alkaloids are used for the following types of cancer:

Acute lymphoid leukemia: In the induction phase, vincristine is used with prednisone.

Acute myelomonocytic or monocytic leukemia: Cytarabine, vineristine, and prednisone.

Hodgkin’s disease: Mechlorethamine, Oncovin (vincristine), procarbazine, and prednisone (MOPP).

Nodular lymphoma: Cyclophosphamide, Oncovin (vincristine), and prednisone (CVP).

Diffuse histiocytic lymphoma: Cyclophosphamide, Adriamycin (doxorubicin), vincristine, and prednisone (CHOP); bleomycin, Adriamycin (doxorubicin), cyclophosphamide, Oncovin (vincristine), and prednisone (BACOP); or cyclophosphamide, Oncovin (vincristine), methotrexate, and cytarabine (COMA).

Wilms’ tumor: Dactinomycin and vincristine.

Ewing’s sarcoma: Cyclophosphamide, dactinomycin, or vincristine.

Embryonal rhabdomyosarcoma: Cyclophosphamide, dactinomycin, or vincristine.

Bronchogenic carcinoma: Doxorubicin, cyclophosphamide, and vincristine.

The chief toxicity associated with vinblastine use is bone marrow depression. The toxicity of vincristine consists of paresthesia, neuritic pain, muscle weakness, and visual disturbances. In addition, both vinblastine and vincristine may cause alopecia.

Dactinomycin

The antibiotics that bind to DNA are nonspecific to the cell-cycle phase. Dactinomycin (actinomycin d and Cosmegen) binds to double-stranded DNA and prevents RNA synthesis by inhibiting DNA-dependent RNA polymerase. It is administered intravenously in the treatment for pediatric solid tumors such as Wilms’ tumor and rhabdomyosarcoma and for gestational choriocarcinoma. Dactinomycin causes skin reactions, gastrointestinal injury, and delayed bone marrow depression.

Mithramycin

The mechanism of action of mithramycin (Mithracin) is similar to that of dactinomycin. It is used in patients with advanced disseminated tumors of the testis and for the treatment of hypercalcemia associated with cancer. Mithramycin may cause gastrointestinal injury, bone marrow depression, hepatic and renal damage, and hemorrhagic tendency.

Daunorubicin and Doxorubicin

Daunorubicin (Daunomycin and Cerubidine) and doxorubicin (Adriamycin) bind to and cause the intercalation of the DNA molecule, thereby inhibiting DNA template function. They also provoke DNA chain scission and chromosomal damage.

Daunorubicin is useful in treating patients with acute lymphocytic or acute granulocytic leukemia. Adriamycin is useful in cases of solid tumors such as sarcoma, metastatic breast cancer, and thyroid cancer. These agents cause stomatitis, alopecia, myelosuppression, and cardiac abnormalities ranging from arrhythmias to cardiomyopathy.

Bleomycin

Bleomycin (Blenoxane) causes chain scission and fragmentation of DNA. With the exception of the skin and lungs, most tissues can enzymatically inactivate bleomycin. Bleomycin is used in the management of squamous cell carcinoma of the head, neck, and esophagus in combination with other drugs in patients with testicular carcinoma and in the treatment of Hodgkin’s disease and other lymphomas. Bleomycin causes stomatitis, ulceration, hyperpigmentation, erythema, and pulmonary flbrosis.

Paclitaxel and Docetaxel

Paclitaxel (Taxol) is a diterpenoid compound that contains a complex taxane ring as its nucleus. The side chain linked to the taxane ring at carbon 13 is essential for its antitumor activity. Modification of the side chain has led to identification of a more potent analogue, docetaxel (Taxotere), which has clinical activity against breast and ovarian cancers. Originally purified as the parent molecule from yew bark, paclitaxel can now be obtained for commercial purposes by semisynthesis from 10-desacetylbaccatin, a precursor found in yew leaves. It also has been successfully synthesized from simple off-the-shelf reagents in a complex series of reactions.

Taxol binds specifically to the B-tubulin subunit of microtubules and appears to antagonize the disassembly of this key cytoskeletal protein, with the result that bundles of microtubules and aberrant structures derived from microtubules appear in paclitaxel-treated cells. Arrest in mitosis follows. Cell killing is dependent on both drug concentrations and duration of cell exposure. Paclitaxel has undergone initial phases of testing in patients with metastatic ovarian and breast cancer; it has significant activity in both diseases, including diseases in patients that have progressed on standard primary combination regimens. Response rates in relapsed patients range from 20 to 50%, depending on the treatment history and the regimen employed. Early trials indicate significant response rates in lung, head and neck, esophageal, and bladder carcinomas as well.

Pactitaxel exerts its primary toxic effects on the bone marrow. Neutropenia usually occurs 8 to 11 d after a dose and reverses rapidly by 15 to 21 d. Many patients experience myalgias for several days after receiving paclitaxel. In high-dose schedules, a stocking-glove sensory neuropathy can be disabling, particularly in patients with underlying diabetic or alcoholic neuropathy.