Agents that intercalate DNA

Doxorubicin (Adriamycin)

Daunorubicin (Daunomycin)

Dactinomycin

Plicamycin (Mithramycin)

Agents that fragment DNA

Bleomycins

Agents that inhibit Topoisomerase II

Etoposide (VP-16)

Teniposide

Amsacrine

Agents that inhibit Microtubules

Vincristine

Vinblastine

Paclitaxel (Taxol)

Hormones and related agents

Prednisone

Tamoxifen

Leuprolide

Androgens

Progestins

Estrogens

Miscellaneous

L-Asparaginase

Agents that intercalate DNA – Doxorubicin, Daunorubicin, Dactinomycin, Plicamycin

Doxorubicin and Daunorubicin

• *Doxorubicin is the most powerful and widely used drug in cancer chemotherapy
• Inhibit both DNA replication and RNA synthesis
• *Intercalate into DNA causing local unwinding
• Inhibit topoisomerase II indirectly
• *NON-PHASE Specific
• IV only
• Inactivated in most tissues by microsomal glycosidases
• *DLT: CARDIOTOXICITY (also myelosuppressive)
• *Resistance: decreased accumulation
• *biliary excretion
• Doxorubicin : acute leukemias, lymphomas, wide array of solid tumors
• Daunorubicin: acute lymphocytic and granulocytic leukemias

Dactinomycin

• first intercalating agent to be discovered
• NON-PHASE Specific
• Extremely potent inhibitor of RNA synthesis
• DLT: bone marrow suppression
• USE: Wilm’s tumor in children, rhabdomyosarcoma

Plicamycin

• similar MOA to dactinomycin, but doesn’t intercalate
• Extreme toxicity – limits treatment
• Most hepatotoxic agent in use
• High doses: used to treat advanced embryonal tumors of the testes
• Low doses: used to treat severe hypercalcemia or hypercalciuria

Agents that fragment DNA – Bleomycins

Bleomycins

• cause DNA strand scission and fragmentation

1.     intercalates into DNA

2.     chelates ferrous iron and donates electron to oxygen, creating reactive oxygen species

3.     NAPD enzyme system in nucleus reduces and reactivates bleomycin

• Degraded by a hydrolase found in many tissues but low in skin and lung
• G₂ phase specific
• Resistance: increased hydrolase or increased repair
• DLT: LUNG FIBROSIS (very little myelosuppression)
• Useful in CAs (VBP for testicular), Hodgkin’s and other lymphomas (ABVD regimen), but not sarcomas (have high hydrolase activity)

Agents that inhibit topoisomerase II – Etoposide, Teniposide, Amsacrine

General

• topoisomerase II is used in unwinding of supercoiled DNA
• breaks, lets DNA pass through, reseals
• inhibition of topoisomerase II allows break but not resealing activity

Epipodophyllotoxins – Etoposide (VP-16) and Teniposide (VM-26)

• Synthetic derivatives of folk remedy extracted from May Apple plant
• *G₂ phase specific
• *Inhibits topoisomerase II
• *does not inhibit DNA synthesis
• *Resistance: decreased accumulation
• *DLT: Leukopenia (thrombocytopenia is mild)
• *Use:

Ø  Etoposide: testicular CA, small cell carcinoma of the lung

Ø  Teniposide: investigational use in refractory ALL in children

Amsacrine (m-AMSA)

• intercalates into DNA
• inhibits topoisomerase II
• Use: investigational use in acute myelogenous leukemia

Agents that inhibit Microtubules – Vincristine, Vinblastine, Paclitaxel

General

• M phase specific
• Interfere with the formation of the mitotic spindle
• All of these drugs interfere with microtubule assembly and block cells in mitosis

Vinblastine

• alkaloid derived from Periwinkle (Vinca) plants
• binds to tubulin heterodimers and thus inhibits microtubule assembly

Ø  blocks chromosome segregation and cell division

Ø  also blocks axonal transport and secretory processes

• IV administration
• Very slow elimination (urine and feces); large V_D­, does not enter CNS
• DLT: Leukopenia (thrombocytopenia is not generally a problem)
• Use: testicular carcinoma (VBP), lymphomas (ABVD), and some solid tumors

Vincristine

• similar to vinblastine
• DLT: Peripheral neuropathy (little myelosuppressive activity; make good for combo therapy)

Ø  suppression of Achilles tendon reflex

Ø  paresthesias of hands and feet

Ø  motor weakness

Ø  reduced bowel motility (severe constipation)

• Use: with prednisone to induce remission in ALL; MOPP regimen for Hodgkin’s
• Used in combo for: AML, lymphomas, Wilm’s tumor, Ewing’s sarcoma, osteogenic sarcoma, embryonal rhabdomyosarcoma

Paclitaxel (Taxol)

• investigational use for breast, ovarian, and several others
• approved for refractory ovarian and breast cancer
• KIND OF DIFFERENT ACTION: STABILIZES microtubules and keeps them from disassembling
• DLT: myelosuppression

Hormones and related Agents – Prednisone, Tamoxifen, Leuprolide

General

• some tumors can be inhibited or stimulated in their growth by steroid hormones
• hormone therapy is a non-toxic way to control the growth of certain tumors
• seldom curative
• difficult to predict response

Prednisone

• adrenocorticosteroid
• Use: VAMP regimen for ALL; MOPP regimen for Hodgkin’s Lymphoma

Androgens

• useful in management of mammary CA but now pretty much replaced by tamoxifen

Progestins

• useful in management of endometrial CA previously treated by surgery and radiation

Estrogens

• useful in androgen dependent prostatic CA, esp with distant metastases

Tamoxifen

• estrogen receptor antagonist
• oral administration

Leuprolide

• Physiological agonist of GnRH
• Use: to down regulate sex hormones; prostatic CA

Miscellaneous Agents – L-Asparaginase

L-asparaginase

• since some tumors have a reduced capacity to synthesize asparagine, L-asparaginase is used to lower the levels of L-asparagine in the blood.
• IV or IM administration
• Little myelosuppression or GI disturbances
• Toxicity: anaphylaxis can occur, hemorrhaging due to inhibition of clotting factors, toxic to liver and pancreas
• Use: Acute lymphocytic leukemia

Tags: Amsacrine, Asparaginase, Bleomycins, Dactinomycin, Daunorubicin, Doxorubicin, Epipodophyllotoxins, microtubules, Plicamycin, Topoisomerase, Vincristine

This entry was posted on Monday, August 17th, 2009 at 5:00 am and is filed under Pharmacology. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.