1) Use drug that targets a single activity against the specific tumor

2) Each drug should have a different MOA and act a different cell cycle phase

3) When possible choose drugs that don't have overlapping toxicity

4) All drugs should be used at optimal dose and most effective scheduling in combination

Cytarabine

Fluorouracil

Mercaptopurine

Methotrexate

Thioguanine

Methotrexate

5' Fluorouracil

Capecitabine

Cyclophosphamide

Carmusitine

Temozolamide

Cisplatin

Daunorubicin

Doxorubicin

Dactinomycin

Bleomycin

Vincristine

Vinblastine

What is the dose-limiting effect of etoposide?

What is Etoposide used to treat?

What is Fulvestrant use to treat?

Solid Tumors (i.e. choriocarcinoma or osteosarcoma)

ALL (Acute Lymphoblastic Leukemia

Nephrotoxic

Myelosuppressive (neutropenia, thrombocytopenia, diarrhea)

Pulmonary Toxicity and Hepatotoxicity with long-term use

GIT-mucositiis

Reduced polyglutamation

Change in receptor affinity

increase DHFR levels

What is the MOA of 5' Flourouracil?

Interferes with RNA function by misincorporating the fluorodinated uridine into RNS; this creates a dysfunction RNA

Also, inhibits Thymidylate Synthase thus blocking DNA synthesis

Anorexia/nausea

Alopecia

Stomatitis/Diarrhea

Myelosuppression in bolus doses

Myelosuppression

Permanent Amenorrhea & azoospermia

Leukemogenic

Cardiotoxic in high doses

Renal & Bladder toxicity

What is the end product of metabolism for Cyclophosphamide?

Active nitrogen mustard (very Nephrotoxic)

&

Acrolein ( causes hemorrhagic cystitis)

Causes Inappropriate secretion of ADH so may cause water intoxication. Also the drug is given with 3 liter of fluid a day to protect the kidney.

With all the water Hyponatremia can result; if this occur fuid intake is decreased.

Intercalates with DNA and bind the helical groove

Prevents Topo II from resealing breaks

Cause Free- Radical formation

Solid breast, endometrial, testes, & lung tumors

Hodgkins & Non-Hodgkins

Development of abnormal transport protein

MDR gene over-express the glycoprotein regulating pump-out

Fast-running IV

*Risk of extravasation

Cardiomyopathy

Suprventricular Arrhythmia w/ repeated doses

*Given with Azathioprine enhances its toxicity and cholestasis may occur

Bind to DNA helix

Prevents transcription of DNA by RNA polymerase

Cause single strand breaks in DNA

What are the Uses of Dactinomycin?

Rhabdomyosarcoma

Wilms Tumor

Ewings Tumor

Kaposi sarcoma

Hematopoietic suppression

Pancytopenia-dose Limiting property

Others: Diarrhea, glossitis, cheilitis and oral ulcers, alopecia, anorexia, n/v

Causes DNA fragmentation

Free-Radical Formation causes chromosomal fragmentation

Cells accumulate in G₂ Phase

Testicular

Squamous carcinoma of head, neck, & lungs

Lymphomas

Pulmonary Toxicity (dry cough)

Pulmonary Fibrosis

Others: little myelosuppression, hyperthermia in lymphoma pts especially, skin blisters, pigmentation, hyperkeratosis

Spindle Poisons; they bind to tubulin and prevent assembly of microtubules.

They act in M phase of the cycle

Peds leukemia

Solid Hodgkins diseases

Rhabdo

Lymphomas

Neuroblastomas

Hodgkins

Testicular carcinoma

Neurotoxic (peripheral & autonomci neuropathy)

Sensory & Motor parasthesis

*Bone marrow spearing

Myelotoxic - reversible

Dose-Limiting Neutropenia

Leucopenia & Alopecia

Topo II stabilizer; cause dsDNA breaks during replication.

Specific for late S and early G₂ phase.

Testicular Cancer

Hodgkins

Diffuse Lymphoma

Oat cell

Dose-Limiting Leukopenia

May cause AML development

Others: Hypersensitivity, Hepatic & renal toxicity @ high dose, Neuromuscular & Skeletal toxicities

Dose Limiting- Neutropenia, thrombocytopenia

Dose-Limiting Mucositis & Diarrhea in pts with hematological malignancies

Primarily used to treat advanced ovarian and metastatic ovarian cancer

Breast Mets

Lung, esophageal, bladder, head and neck cancers

Hypersensitivity rxn

severe but reversible neutropenia

Cardiac conduction defects

alopecia

n/v

PERIPHERAL NEUROPATHY

*Clearance reduced by Cisplatin

Breast cancer and PROPHYLAXIS

Given to pt who had chemo, radiation, or surg

Given to older women to shrink tumors that are inoperable

Infertility, gynecomastia

N/V

Hot Flashes

Vag bleeding,

hypercalcemia

ocular dsyfunc

peripheral edema

Treatment in women with breast cancer which have become resistant to Tamoxifen

Only give to Post-menopauseal women.

Given IM monthly

Bone pain & Back pain

gynecomastia

hematuria

Impotence

Testicular atrophy

*Can cause hypogonadism!!!!!

Hypersensitivity rxn

High levels (Precipitate coma)

Clottin abnormalities

Intracranial Hemmorrhage (rare, within first week of tx)

N/V

Chills

Fevers

Headaches

Ventricular dysfunction & heart failure association

Nephrotoxicity

Electrolyte disturbance (decrease in them)

Ototoxicity

*Marked N/V (reduced by given Ondansetron=antiemetic)

What drugs DO NOT exhibit dose-limited toxicity to bone marrow!

*No myelosuppression

Hormones

Vincristine

Bleomycin

Asparaginase

Cisplatin

Common & serious: Doxorubicin and other anthracyclines

Not so common: Paclitaxel, Trastuzumab, & 5'FU= Angina and MI

Cytarabine

Asparaginase

Vincristine

Cisplatin

Flourouracil

Methotrexate

Dose-Limiting Toxicities- Match:

1) Methotrexate

2) Cisplatin

3) Doxorubicin

4) Daunorubicin

5) Bleomycin

6) Vincristine/blastine

7) Etoposide

8) Topetecan

1) Myelotoxic

2) Kidney

3) Cardiac

4) Cardiac

5) Pulmonary

6) Neurologic

7) Leukopenia

8) Neutropenia & thrombocytopenia

Most- Cisplatin

Least - Vinca alkaloids

Most- alkylating agents

Least - antimetabolites