Microtubule

inhibitors

Microtubules Microtubules InhibitorsInhibitors

These drugs disrupt These drugs disrupt microtubules, which are , which are structures that pull the cell structures that pull the cell apart when it dividesapart when it divides

are derived from natural are derived from natural substances such as plant substances such as plant alkaloids

ANTIMICROTUBULE AGENTSANTIMICROTUBULE AGENTS

Microtubules Microtubules InhibitorsInhibitors

CCS Vinca alkaloids

Vinblastine Vincristine

TaxanesPaclitaxelDocetaxel

Podophyllotoxine

Vinblastine and VincristineVinblastine and Vincristine

Both drugs are cell cycle-specific Both drugs are cell cycle-specific because they block mitosis in because they block mitosis in

metaphase metaphase They bind to the microtubular They bind to the microtubular

protein, tubulin and thus protein, tubulin and thus preventing the cell from making preventing the cell from making

the spindles the spindles This results in This results in arrest of mitosis

at metaphase

Therapeutic UsesTherapeutic Uses Vinblastine Vinblastine is used in testicular is used in testicular

carcinoma, Hodgkin’s disease carcinoma, Hodgkin’s disease VincristineVincristine is used in the treatment of is used in the treatment of

acute leukemia in children, Wilm’s tumor, acute leukemia in children, Wilm’s tumor, and Hodgkin’s and non-Hodgkin’s and Hodgkin’s and non-Hodgkin’s lymphomaslymphomas

Adverse Effects:Adverse Effects: Common adverse effects for both drugs Common adverse effects for both drugs

include include cellulitis or phlebitis cellulitis or phlebitis if the drugs if the drugs extra vasate during injectionextra vasate during injection

Nausea, vomiting, diarrhea, and alopeciaNausea, vomiting, diarrhea, and alopecia

Toxicity of Vinblastine & Toxicity of Vinblastine & Vincristine Vincristine

Vinblastine Myelo-supression

Vincristine

NOT myelosuppress

ant

Peripheral neuropathy:

Depressed deep tendon reflex,

paresthesia, foot drop

TaxanesTaxanes

Interferes with cell division by Interferes with cell division by keeping the spindles from being keeping the spindles from being broken down (freeze)broken down (freeze)

Paclitaxel (Taxol) Paclitaxel (Taxol) shows good shows good activity against activity against metastatic metastatic breast breast cancer cancer and advanced and advanced ovarian cancerovarian cancer

Side effects; Side effects; neutropenia ‼, neutropenia ‼, peripheral neuropathyperipheral neuropathy

Filgrastim ( granulocyte colony stimulating Filgrastim ( granulocyte colony stimulating factor)factor)

V. Miscellaneous

Anticancer Agents

V- Miscellaneous AgentsV- Miscellaneous Agents

L-AsparaginaseL-Asparaginase HydroxyureaHydroxyurea MitotaneMitotane Retenoic acid derivativesRetenoic acid derivatives InterferonInterferon

L- AsparaginaseL- Asparaginase Asparagine is amino acid required Asparagine is amino acid required

for protein synthesis) for protein synthesis) Neoplastic cells require an Neoplastic cells require an

external source of asparagine external source of asparagine (from the plasma) because of their (from the plasma) because of their limited capacity to make sufficient limited capacity to make sufficient

asparagine to support growthasparagine to support growth

L-Asparaginase L-Asparaginase

L-asparaginaseL-asparaginase

Asparagine Asparagine aspartic acid aspartic acid

+Ammonia+Ammonia L-asparaginase hydrolyzes serum L-asparaginase hydrolyzes serum

asparagine and thus deprives the tumor asparagine and thus deprives the tumor cells of this nutrient required for protein cells of this nutrient required for protein

synthesissynthesis Most normal cells can synthesize Most normal cells can synthesize

asparagine and thus are less susceptible to asparagine and thus are less susceptible to the action of asparaginasethe action of asparaginase

Theraputic uses:Theraputic uses: L-asparginase is used to treat L-asparginase is used to treat childhood childhood acute lymphocytic acute lymphocytic leukemialeukemia in combination with in combination with

vincristine and prednisonevincristine and prednisone AAdverse effects: dverse effects:

Hypersensitivity reactions, Hypersensitivity reactions, liver affection and pancreatitisliver affection and pancreatitis

HydroxyureaHydroxyurea

Hydroxyurea interferes with conversion Hydroxyurea interferes with conversion of ribonucleotides to of ribonucleotides to deoxyribonucleotides by inhibiting deoxyribonucleotides by inhibiting Ribonucleotide Diphosphate ReductaseRibonucleotide Diphosphate Reductase. . In addition, hydroxyurea blocks the In addition, hydroxyurea blocks the incorporation of the thymidine incorporation of the thymidine nucleotide into the DNA strand.nucleotide into the DNA strand.

Melanoma; recurrent metastatic or Melanoma; recurrent metastatic or inoperable carcinoma of the ovaryinoperable carcinoma of the ovary

MitotaneMitotane   

   Adrenal carcinomaAdrenal carcinomaReduces excessive steroid Reduces excessive steroid

secretionsecretion Retenoic acid derivativesRetenoic acid derivatives

Remissions -- acute leukemiaRemissions -- acute leukemia

Drug combinations

The administration of combinations of The administration of combinations of drugs in the treatment of cancer drugs in the treatment of cancer

produces produces better results than a single better results than a single drug drug

A combination of drugs with A combination of drugs with different different toxic effectstoxic effects and and affecting affecting

different biochemical pathwaysdifferent biochemical pathways has higher anti-tumour activity without has higher anti-tumour activity without

additive toxicityadditive toxicity Therapy is Therapy is given intermittentlygiven intermittently to to allow recovery of normal tissue i.e. bone allow recovery of normal tissue i.e. bone

marrow and immune system that has marrow and immune system that has been affected by the drugsbeen affected by the drugs

Examples of drug Examples of drug combinations combinations

Acute lymphocytic leukemia:Acute lymphocytic leukemia: vincristine, methotrexate and 6-vincristine, methotrexate and 6-mercaptopurinemercaptopurine

Hodgkin's disease:Hodgkin's disease: vinblastine, vinblastine, doxorubicin and bleomycindoxorubicin and bleomycin

Non-Hodgkin's lymphomas:Non-Hodgkin's lymphomas: cyclophosphamide, doxorubicin, cyclophosphamide, doxorubicin, vincristine vincristine

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