Sessions 73 and 74
Terms
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- Cancer Biology/Cell Kinetics
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Similar to bacterial kinetics
Doubling time = 1 g to 2 g
Generation time = 1 cell to 2 cells (controls growth rate)
Growth is exponential - Cell Cycle
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G1 = protein and RNA synthesis
S = DNA synthesis
G2 = protein and RNA synthesis
M = mitosis/cell division
G0 = non-dividing - Total Kill Concept
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One L1210 Leukemia cell is FATAL to a mouse
- a given dose will kill a constant percentage of cells per unit time
- # of original cells before therapy will determine # of cells surviving therapy - Combination Chemotherapy
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ABVD
BACOP
CHOP
CMF
CVP
MOPP
POMP - Carmustine-Cimetidine
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Additive bone marrow depression
Cimetidine inhibits Carmustine metabolism - Cyclophosphamide-Allopurinol
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Bone marrow depression
Allopurinal alters the liver metabolism of cyclophosphamide - Mercaptopurine - Allopurinol
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Increased mercaptopurine toxicity
Allopurinol inhibits xanthine oxidase which is involved in mercaptopurine metabolism - Methotrexate - Ethyl Alcohol
- Hepatotoxicity
- Methotrexate-Aspirin
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Increased serum concentration of free MTX
Aspirin displaces MTX from plasma proteins and competes for its elimination - MTX-Cytarabine
- Syngeristic effects
- MTX-Neomycin
- Decreased MTX absorption
- MTX-Probenecid
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Increased MTX in serum
Probenecid inhibits MTX excretion - MTX-Sodium Bicarb
- Increased renal elimination of MTX due to alkalinization of urine
- MTX-Sulfisoxazole
- Decreased plasma binding and renal clearance of MTX
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Antineoplastic Agents
General Toxicities -
-pancytopenia
-thinning and denudation of mucosa
-hair loss, skin lesions
-teratogenic, sterility
-immunosuppression
-cancer
-gout - Alkylating Agents MOA
- alkylate nucleic acids and proteins
- Alkylating Agents Kinetics
- quickly metabolized, distributed, excreted
- Alkylating Agents Toxicities
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Nausea, vomiting
Alopecia
Thrombocytopenia
Hemorrhagic cystitis
Increased skin pigmentation - Alkylating Agents Resistance
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Decreased take up of drug
Increased ability to excise cross-linked residues and repair the defect - Mechlorethamine Uses
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Hodgkin's
Lymphosarcoma
Wilm's Tumor - Chlorambucil Uses
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Lymphosarcoma
CLL
Ovarian CA
Hodgkin's - Cyclophosphamide Uses
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ALL
Neuroblastoma
Myeloma
Wilm's tumor - Melphalan uses
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Multiple myeloma
Melanoma - ThioTEPA uses
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Ovarian CA
Lymphosarcoma - Busulfan Uses
- CML
- Uracial Mustard Uses
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CLL
Lymphoma
Hodgkin's - Pipobroman Uses
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Polycythemia vera
Chronic granulocytic leukemias - BCNU Uses
- Astrocytoma (CNS tumors)
- Procarbazine Uses
- Hodgkin's
- Dacarbazine Uses
- Hodgkin's
- Altretamine Uses
- Ovarian CA
- cis-DDP MOA
- Alkylates DNA, forms coordination complexes
- cis-DDP Toxicity
- Kidney damage
- cis-DDP uses
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Testicular CA
Ovarian CA
Bladder CA
Head and neck CA - Carboplatin
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Similar to cis-DDP
Less toxic - 6-Mercaptopurine
- Purine analogue/anti-metabolite
- 6-Mercaptopurine MOA
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Suppression of de novo purine biosyntheis (due to psuedo-feedback inhibition)
Inhibition of adenylate and guanylate formation
Inhibition of interconversion reactions in purine metabolism - 6-Mercaptopurine Kinetics
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Oral
Complete GI absorption
90% protein bound
t1/2 = 90 minutes - 6-Mercaptopurine Toxicities
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Leukopenia, thrombocytopenia, anemia
Anorexia
Jaundice - 6-Mercaptopurine Uses
- Antileukemic
- Azathioprine
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Less toxic than 6-MP
Prevents transplant rejection
Used in RA and SLE - Pyrimidine Analogues
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5-FU
ARA-C - 5-FU MOA
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Blocks thymidylate/DNA synthesis
Depresses RNA synthesis - 5-FU Kinetics
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IV
Excreted as expired CO2 after 24 hours - 5-FU Toxicities
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Leukopenia, thrombocytopenia
Anorexia, diarrhea, stomatitis - 5-FU USes
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GI neoplams
Female genital tract CA
Breast CA - ARA-C MOA
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Inhibits DNA synthesis
Incorporated into internucleotide linkages - ARA-C Kinetics
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IV
Cleared in 15-30 minutes
Metabolism inactivates - ARA-C Toxicities
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Leukopenia, thrombocytopenia, anemia
Anorexia, nausea, vomiting - ARA-C Uses
- Acute granulocytic leukemias
- Folic Acid Analogues (MTX)Kinetics
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Absorbed well
Peak levels in 1 hour
50% protein bound
24 hour, complete excretion - MTX Toxicities
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Anorexia, weight loss, bloody diarrhea
Leukopenia
Depression, coma
Severe hemorrhagic enteritis
Dermatitis, GI ulceration, infection, bleeding - MTX Uses
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Choriocarcinoma
ALL
Psoriasis - Vinca Alkaloids (Vinblastine/Vincristine)MOA
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Bind microtubular proteins
Prevent spindle formation
Inhibit cell cycle - Vinca Alkaloids (Vinblastine/Vincristine) Toxicities
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Bone marrow depression
Pancytopenia
Neurological Problems - Vinca Alkaloids (Vinblastine/Vincristine) Uses
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Solid tumors
Lymphosarcoma
Hodgkin's
Lymphoma
Choriocarcinoma
Acute leukemias - Epipodophyllotoxins
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Etoposide
Teniposide - Epipodophyllotoxins MOA
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Block S-G2 phase of cell cyle
Affect topoisomerase II - Epipodophyllotoxins Toxicities
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Leukopenia, thrombocytopenia
Nausea, vomiting, stomatitis, diarrhea
Alopecia
Hepatic toxicity - Epipodophyllotoxins USes
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Testicular tumors
NHL
AML
Breast CA
Kaposi's sarcoma
ALL - Taxol MOA
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Binds tubulin dimers
Disrupts mitosis - Taxol Toxicities
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Myelosuppression
Alopecia
Peripheral neuropathies
Muscle and joint pain
CV problems
Hypersensitivity - Taxol Uses
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Breast CA
Ovarian CA
Lung CA
Head and neck CA - Daunorubicin/Adriamycin MOA
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Intercalate DNA
Prevent replication
Inhibit topoisomerase II - Daunorubicin/Adriamycin Kinetics
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t1/2 = 45 minutes
Bile excretion - Daunorubicin Toxicities
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Bone marrow depression
Tachycardia, arrhythmias
Cardiorespiratory symptoms - Adriamycin Toxicities
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Bone marrow depression
CHF
Nausea - Daunorubicin Uses
- Acute leukemias
- Adriamycin Uses
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Lung CA
Breast CA
Bladder CA
Lymphoma
Sarcomas - Plicamycin MOA
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Binds DNA
inhibits RNA synthesis
Requires guanine - Plicamycin Uses
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Embryonal cell testicular tumors
Paget's, hypercalcemia - Dactinomycin MOA
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Prevents DNA synthesis by binding DNA
Guanine and helical configuration required - Dactinomycin Kinetics
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IV
Bile and urine excretion - Dactinomycin Toxicities
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Hematopoietic depression, leukopenia, anemia, pancytopenia
Nausea, vomiting, stomatitis
Erythema, acne, alopecia
Fatigue, fever, myalgia - Dactinomycin Uses
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Wilm's Tumor
Rhabdomyosarcoma
Ewing's sarcoma
Osteogenic sarcoma
Choriocarcinoma
Uterine and testicular CA - Bleomycin MOA
- Inhibit DNA synthesis
- Bleomycin Toxicities
- Pulmonary fibrosis
- Bleomycin Uses
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Squamous cell carcinoma of skin
Testicular tumor
Lymphoma - Mitomycin MOA
- Alkylating agent
- Mitomycin Toxicities
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Myelosuppression
Renal toxicity - Mitomycin Uses
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Gastric adenocarcinoma
Tumors of cervix, colon, rectum, pancreas, breast, bladder, lung - Prednisone MOA
- Inhibit RNA and protein synthesis
- Prednisone Toxicities
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Fluid disturbances
Hyperglycemia, glycosuria
Peptic ulceration
Infection
Psychiatric disturbances
Skeletal atrophy - Predinose Uses
- ALL
- Other Hormone Therapies
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Progesterone (endometrial CA)
Diethylbestrol
Flutamide (antiandrogen)
Estramustine (estrogen + alkylating agent)
Leuprolide (GnRH analog)
Testosterone proprionate
Antiestrogens
Aminoglutethimide - Estrogen/Androgen MOA
- Change hormonal environment of tumor
- Estrogen/Androgen Uses
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Prostatic CA
Mammary CA - Monoclonal Antibody (Herceptin) MOA
- Inhibits tumor cell growth by binding to HER2
- Monoclonal Antibody (Herceptin) Toxicities
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Weakening of heart muscles leading to CHF
Leukopenia, anemia
Diarrhea, abdominal pain
Chills, fever, pain, weakness, anusea, vomiting, headache - Monoclonal Antibody (Herceptin) Uses
- Advanced breast CA
- Hydroxyurea MOA
- inhibits ribonucleoside diphosphate reductase
- Hydroxyurea Uses
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Chronic granulocytic leukemia
Polycythemia vera
Solid tumors - Mitotane Uses
- Adrenocortical CA (Palliative tx)
- L-asparaginase Uses
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ALL
(SE: nausea, liver dysfunction, hypersensitivity) - Gold-198 Uses
- Pleural effusions and ascites secondary to cancer
- Sodium Phosphate P 32 Uses
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Polycythemia Vera
CML