CHEMOTHERAPY OF NEOPLASTIC DISEASES
Outline, VPH 445

Copyright, Purdue Research Foundation, 1996

table2.htm table3.htm Note: "**" = material added since BMS445 handout was printed

Topics

Overview
Cancer Biology
Drugs

Overview

Cancer chemotherapy challenging
Often not curative
Palliative treatment
Importance of supportive therapy
Cytotoxic drugs -- "toxic"
Biological response modifiers -- much current research
Expense

Factors determining therapeutic goals

Examples of Factors Determining Therapeutic Goals
Patient	Neoplasm	Facilitites / Treatments Available	Owner
Species	Type	Primary modalities	Financial status
Breed	Natural history	Secondary support, e.g., clinical pathology, isolation facilities)	Commitment
Age	Stage (extent)	Proximity	Living circumstance
Sex	Location	-	Need for animal
Health status	Grade	-	Ability to care for animal
Function / role	-	-	-

Cancer Biology

Topics

Therapeutic problem
Tumor growth
Tumor heterogeneity
Cell Kill Hypothesis
Resistance
Modalities
Toxicity

Therapeutic problem

Selectivity
- Must kill ALL cancer cells
  9 to 11 "log" kill
- Minimal harm to normal cells
  <2 "log" kill!!!
- Differences mostly in "rates"
Moving target -- changes in sensitivity
- Drug sensitivity changes during therapy
- Cells resistant at outset may become predominant
Key definitions -- Figure
- [fig]Graph of results of chemotherapy
- Cure -- Must kill ALL cancer cells
- Remission (Complete response) -- Tumor no longer detectable
- Induction regimen -- to induce remission
- Maintenance regimen -- followup treatment to remove metastatic foci and microscopic remnants
- Relapse -- tumor clinically detectable after prior remission
- Palliative therapy -- improve quality of life
- Curative therapy -- aimed at "cure" of cancer

Tumor growth

Cytotoxic drugs most effective in rapidly growing tumors
[fig] Figure (4-11, Shackney '93)
Growth rate slows as tumor increases in size (Gompertzian Growth)
[fig] Figure (4-1, Shackney '93)
Growth rate (doubling time) determined by --
- Production --
  - Fraction of tumor dividing
    Stem cells -- cells actively dividing
    Clonogenic cells -- cells that divide in culture
  - Cell cycle time
- Loss -- Fraction of cells dieing
- [fig] Figure -- Clinical Growth Rate -- Mathematical model
- Cell cycle
  - G₁ phase -- highly variable
  - S phase -- 8-20 hr duration
  - G₂ phase -- ~3 hr cancer cells
  - M phase -- 1 hr
  - G₀ phase -- Not cycling
Doubling Times and Growth Fractions of Some Humor Tumors

Sample Tumor Doubling Times and Growth Fraction
Tumor	Doubling Time (Days)	Growth Fraction
Burkitt's lymphoma	2 - 5	0.29
Testicular cancer	21	--
Osteogenic sarcoma	34	--
Hodgkin's disease	38	--
Colon adenocarcinoma	96	0.03
Breast adenocarcinoma	129	0.02
Lung adenocarcinoma	134	--
Shackney 1993

Cell Kill is First Order

Skipper's Cell Kill Hypothesis
"log"cell kill
"Cure" only if all cells killed
Killing is first order process
Each treatment cycle kills same Fraction of cells
Each treatment cycle kills different Number of cells
Table: Example of values in cell-kill

Cell Fraction Killed	Fraction Surviving	Log Surviving	Log Kill
0.9	0.1	- 1	1
0.99	0.01	- 2	2
0.999	0.001	- 3	3
0.999999999	0.000000001	- 9	9

Sources of Heterogeneity in Tumors

Pharmacokinetic
Kinetic
Genetic

[fig] Figure: Log Kill & Host Survival

Heterogeneity -- Pharmacokinetic

Variation in Drug delivered to tumor cells
- Blood supply
- Necrosis
- Route

Heterogeneity -- Kinetic

Variation in Cell cycle time among cells
Cells not all in same cell cycle-phase
[fig] Figure: Cell cycle stages
[fig] Figure: Bleomycin effect on different phases

Heterogeneity -- Genetic -- Resistance Mechanisms

Defective activation
- Cyclophosphamide requires metabolic activation
- Methotrexate conversion to more active MTX-polyglutamate in cells
Increased inactivation
- e.g., aldehyde dehydrogenase -- cyclophosphamide to inactive metabolite
- cell protective groups scavenge highly reactivte compounds -- sulfhydryl compounds -- glutathione, metallothionine
Altered nucleotide pools
- Can occur with antimetabolites
Altered DNA repair
- Repair mechanisms increased, i.e., ability to remove cross-links
- Bleomycin and other DNA-directed drugs
Altered target
- Enzyme active, but less affinity for drug
- Methotrexate
  - Dihydrofolate reductase changes
Decreased target
- decreased topoisomerase II
- e.g., etoposide
Gene amplification
- Methotrexate (MTX)
  - Increase dihydrofolate reductase
  - Requires more MTX to block
Decreased accumulation
- Decreased uptake
  - Methotrexate -- carrier protein decreases
  - Mechlorethamine -- decreased choline carrier
  - Melphalan / leucine transport
- Increased Efflux
  - Multidrug Resistance
  - usually alkaloids such as doxorubicin, etoposide, actinomycin D, vinca alkaloids
  - P-Glycoprotein (gP-170) in membrane, pumps drug out
  - Pump normally expressed in some cells e.g., bone marrow stem cells
  - Some drugs can reverse resistance -- e.g., calcium channel blockers

Treatment Modalities

Adjuvant Therapy
Combination Therapy
- Minimizes development of resistance
- Same or greater cell kill with less toxicity
- Drugs should have different limiting toxicities
- Timing can be important
- Scheduled multiple drugs
  - Example: MOPP for Hodgkins
  - M: mechlorethamine; O: Vincristine (Oncovin); P: Procarbazine; P: Prednisolone
- Alternating Combinations

Toxicities Frequently Observed

Tissues / responses

Rapid growth rate tissues
- Bone marrow suppression
- GI toxicity (mucositis, stomatitis, etc.)
Other
- Anorexia and vomiting
- Hypersensitivity
See Brody, et. al., P 588-589 general and specific toxicities
See Calabresi et al, '93, Table 21-1

Toxicities Related to Specific Drugs

Renal
- Cisplatin, Methotrexate (high dose)
Hepatic
- Folic acid antagonists (e.g., methotrexate)
CNS
- Vincristine (Oncovin^R)
Cardiac
- Doxorubicin (Adriamycin^R) and derivatives
Long term toxicities
- Types
  - Oncogenesis
  - Mutagenesis
  - Teratogenesis
- Typical Drugs
  - Alkylating agents
  - Antitumor antibiotics
- Need for care in handling

Drugs

Nucleic Acid Nomenclature

Nucleic Acid Nomenclature
Base	nucleoSIDE	nucleoTIDE
Adenine (A)	AdenoSINE	AdenYLATE (AMP)
Guanine (G)	GuanoSINE	GuanYLATE (GMP)
Uracil (U)	UriDINE	UridYLATE (UMP)
Cytosine (C)	CytiDINE	CytidYLATE (CMP)
Thymine (T)	DeoxythymiDINE	DeoxythymidYLATE (dTMP)

Nucleic Acid -- Base Pairs
	Base Pairs
RNA	Purine (G & A) - Pyrimidine (C & T)
	G - C pair (3 H-bonds)
	A - U pair (2 H-bonds)
DNA	Purine (G & A) - Pyrimidine (C & U)
	G - C pair (3 H-bonds)
	A - T pair (2 H-bonds)

Antimetabolites

Group Characteristics

Resemble NORMAL substrates
Most inhibit DNA synthesis
Some inhibit RNA synthesis and/or function
Bone Marrow cell replication is profoundly inhibited
GI toxicity great with some
Highly cell cycle specific
- Also "phase specific", e.g., S or M phase

Methotrexate

Structure

Mechanism of action

Folic Acid Analogue
Carrier transport into cell
Binds strongly to DHFR to deplete THF
- Decreases 1-carbon transfers in Purine synth.
- Decreases [1-C-THF]intracellular which decreases dUMP dTMP
- Therefore, decreases NUCLEIC ACID synthesis
Forms polyglutamyl-MTX which traps MTX inside cell & inhibits thymidylate synthase
[fig] Figure -- Mechanism of action

Adverse effects

Dose limiting
- Myelosuppression
  - Thrombocytopenia and Leukopenia
  - Nadirs 7-10 days after Rx, Recovery 14-21 days
- GI toxicity
  - Oral mucositis is early sign of GI toxicity
  - Severe mucositis
  - Small bowel ulceration & bleeding
  - Diarrhea -- requires cessation to prevent perforation of gut
Nephrotoxicity
- Conventional doses, infrequent toxicity
- High doses, toxicity can be severe
  - Precipitation of metabolites
  - Alkalinize urine & hydrate patient to dilute & increase solubility of metabolites
  - Leucovorin (folinic acid, N5-THF)
- Reversed within 3 weeks spontaneously if exposure not prolonged
Immunosuppression
Hepatotoxicity
- With chronic administration as in ALL of childhood and psoriasis Rx
- Changes typical of portal fibrosis and cirrhosis.
Listlessness, anorexia, nausea, vomiting
Intrathecal administration
- Acute meningeal irritation with attendant signs, some severe

Clinical Uses

Broad range
Well established
- Acute Lymphoblastic Leukemia of childhood
- Choriocarcinoma
- Cancers of breast, bladder, and head & neck
Useful in non-Hodgkin's lymphomas

Flurouracil, (5-FU)

Structure

[fig] Figure -- Structure of 5-FU and Fluorodeoxyuridine

Mechanism of action

Activated by conversion to nucleotide
[fig] Inhibits DNA synthesis
- Inhibition of Thymidylate synthase
- Most important MOA in rapidly growing tumors (?)
[fig] 5-FU Incorporated into RNA
- Interfere with RNA processing - ALL types
- May be most important MOA in slowly growing tumors

5-FU: Biotransformation

Activation to active compounds
Inactivation to dihydrofluorouracil
- e.g., dihydrouracil dehydrogenase
  - rapid
  - high content in liver
  - Present in intestinal mucosa
  - Less in many GI tumor cells

Adverse effects

Dose limiting
- Bone marrow -- esp. with bolus admin.
  - Leukopenia & Thrombocytopenia
    - nadir 9-14 days after 5 days of Rx
    - recovery by day 21
- GI Toxicity -- esp. with infusion admin.
  - usually Stomatitis & Diarrhea 4-7 days after Rx

Effect of route and schedule on adverse effects

IV bolus
- myelosuppression is dominant
- Prolonged Rx, may cause megaloblastic anemia
Continuous IV Infusion
- Frequently produce, stomatitis, nausea, vomiting, and diarrhea
- Hepatotoxicity (elevated transaminases)
- myelosuppression less common

Effect of peak 5-FU concentration

Acute, reversible cerebellar syndrome
- somnolence, ataxia of trunk or extremities, unsteady gait, slurred speech, nystagmus
- Regimens that produce high peak concentrations in CSF

Other adverse effects

Hyperpigmentation of skin is frequent and may be accompanied by photosensitivity
Toxic effect of radiation to skin may be enhanced
Alopecia, acute and chronic conjunctivitis, and nail changes may be observed

Clinical Use of 5-FU

Single agent
- Palliative in advanced colorectal carcinoma
Combination
- Breast cancer
- Carcinomas of ovary, stomach, pancreas
Sequential MTX + 5-FU
- Head and neck cancer
- [fig] Figure showing MTX & FU on Thymidine kinase

Alkylating Agents

Developed from nitrogen mustard war gases of WW I which were highly reactive vesicants
First chemicals used for cancer Rx
Not cell cycle specific, but still more active in dividing tissues
"Radiomimetic" -- action on DNA resembles radiation

Mechanism of action

[fig] Highly reactive -- form covalent bonds
- Strong electrophilic -- carbonium ion intermediates
- Intermediates react with nucleophiles to form covalent bonds, e.g.,
  - phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups
Consequences
- Bi-functional agents
- DNA-DNA strand and DNA-Protein cross-links
  - especially by reacting with 7-Nitrogen of guanine
- Misreading of genetic code
  - Alkylation of guanine may shift electon configuration so it forms GT rather than GC pairs
- DNA Chain breaks - labilized imidazole

Adverse effects of alkylating agents

More toxic to bone marrow and gut than to liver and kidney, etc.
Infertility to both males and females
Mutagenic
Carcinogenic

Tumor resistance

Develops slowly & may require several genetic / biochemical changes
Increased intracellular nucleophiles
- metallothionein, glutathione
Increased DNA repair systems
Reduced drug accumulation
Resistance not necessarily uniform across group

Clinical Uses

Wide spectrum
Lymphoreticular tissue tumors
Limited activity against sarcomas

Cyclosphosphamide

Structure

[fig] Structure of Cyclophosphamide

Mechanism of action

Hepatic cytochrome P-450 system, enzymes phosphatase and phosphamidase are primary activators (hydrolyze P-N bond) to intermediate, aldophosphamide, which nonenzymatically breaks down to --
- Phosphoramide mustard (bifunctional)
- Acrolein

Clinical Pharmacology

Oral bioavailability = 90-100%
Not vesicant
IV injection no local irritation
Half-life --
- cyclophosphamide -- 3-10 h
- aldophosphamide -- 1.6 h
- phosphoramide mustard -- 8.7 h
Most metabolized-- < 14% unchanged in urine

Adverse effects

Bone marrow suppression most imp.
- leukopenia
- thrombocytopenia
Nausea and vomiting said to be rare

Sterile necrotizing hemorrhagic cystitis

Acrolein is probable cause
Associated with chronic administration
Cause for stopping Rx
Minimize
- high water intake and take in AM
Rx
- Bladder irrigationwith thiol compounds
- Systemic Rx with N-acetylcysteine and mesna

Mesna for Px & Rx of Cystitis

Used prophylactically and therapeutically
Mesna (2-mercaptoethansulfonate, Mesonex)
injectable as inert disulfide which is reduced in renal tubules to mesna
Mesna binds to and detoxifies urotoxc metabolites of cyclophosphamide and Ifosfamide

Clinical Applications

Most widely used alkylating agent, in part due to availability of oral route
Active lymphoproliferative diseases, e.g.,
- Hodgkin's disease
- Chronic lymphocytic leukemia
Significant activity vs
- multiple myeloma
- ovarian, breast, small cell lung carcinoma
Many combinations

Natural Products

Vinca Alkaloids

Vincristine sulfate(Oncovin)
Vinblastine sulfate (Velban)
From periwinkle plant (Vinca rosea L)

Mechanism of action

Uptake by energy dependent carrier
Bind to tubulin in microtubules to cause their dissolution
- Colchicine-like arrest in metaphase
- Altered intracellular transport
Contrast to Taxol which stabilizes tubules
No cross resistance between vincristine and vinblastine

Adverse effects

Severe vesicant
- Must be careful of IV equipment to avoid slough
Neurotoxicity
- Mild sensory neuropathy with sensory impairment and paresthesia: Keep Rx
- Severe paresthesias, loss of reflexes, ataxia, and muscle wasting: stop Rx
- Constipation and abdominal pain - take laxatives
Less hematologic effects than many other cytotoxic drugs
Inappropriate ADH secretion

Uses

Drug of choice for childhood leukemias in combination with prednisone
Used for lymphoreticular neoplasms, carcinomas, and sarcomas

Antitumor Antibiotics

General characteristics

from Streptomyces spp.
All interact with DNA and/or RNA, but may also interact with other cellular substituents
Schedule dependence
- LESS "phase-specific" than antimetabolites
Tissue necrosis is only generalizable toxicity
All IV except bleomycin

Doxorubicin HCl (Adriamycin^R)

Mechanism of action

Rigid, tetracyclic structure substituted with sugar -- daunosamine
DNA topoisomerase II inhibitor
- Crucial to DNA replication and transcription
Traditional explanations of MOA
- intercalates between base pairs of DNA and inhibits DNA-dependent RNA synthesis
- Generates free radicals that cause membrane damage and DNA strand breaks

Resistance

Alterations in Topoisomerase II act.
- Relative importance not established
Increased inactivation of radicals
- Increase in glutathione-dependent enzymes, e.g., glutathione-peroxidase
- Altered NADPH contents
Increase drug efflux
- Multi-drug resistance (MDR)
- P-glycoprotein (gP-170) pump is product of mdr gene

Adverse effects

Three categories of toxicity
- Local toxicities
- Acute toxicities
- Chronic toxicity
Local Toxicity -- Extravasation
- Extravasation -- DON'T!
- Severe local tissue necrosis to point of damaging underlying structures
- If occurs, treat immediately
  - Remove blood from IV line
  - Apply ice, steroid cream
  - Locally adm. sodium bicarbonate and hydrocortisone
  - DHM3 (investigational) shows promise
Local Toxicity -- Radiation Recall
- Interaction of doxorubicin and radiation in some tissues to produce enhanced reactions
- Reactions include
  - Skin: intensity from erhthema to ulceration and necrosis
  - Pulmonary: fibrosis and sloughing of esophageal mucosa
  - Heart, and intestinal mucosa may also be affected
Acute Toxicities
- Hematologic:
  - Leukopenia with nadir 7-10 days; recovery typically by 21 days
  - Thrombocytopenia and anemia less common
- If give too fast
  - "Histamine-release" syndrome
  - Cardiac arrest preceded by ECG changes
Chronic Toxicities
- Cardiomyopathy and congestive heart failure
  - require cessation of Rx after cumulative dose of -- Human: 550 to 600 mg/m²
    Dog:: 250 mg/m²
  - Must maintain record of total dose
- To Reduce incidence
  - Dexrazoxane (ZinecardR) Chelating agent for reducing incidence and severity of cardiomyopathy from Doxorubicin.

Clinical Indications

Broad spectrum anti-cancer activity
Hodgkin's disease, non-Hodgkin's lymphomas, sarcomas, acute, leukemia, and breast, lung, and ovarian carcinomas all responsive
Activity observed in
- bladder tumors, and carcinomas of prostate, thyroid, endometrium, head and neck, and other solid tumors

Dexrazoxane

Chelating agent --
- Derivative of EDTA that cross cell membranes
May be converted intracellularly to "ring-opened" chelating agent that interferes with iron-mediated free radical formation
Start after have reached 300 mg/m2
Not use concurrently with initiation of FU, Doxo, Cyclophosphamide

Bleomycin

Streptomyces verticillus produced mixture of small-molecular-weight copper-chelating glycopeptides

Mechanism of action

To be active, must have Fe2+ replace Cu
Has antitumor, antiviral, and antibacterial action
DNA toxicity
- binds to double- and single-stranded DNA
- produces site-specific and non-specific single- and double-strand chain breaks
  - ratio single:double = 10:1
  - Cleaved at G-C and G-T sequences
- DNA in open chromatin esp. sensitive
Non-covalent interstrand links
Inhib repair enzyme: DNA ligase
Cell-cycle specific: most G2

Adverse effects

Toxicity is UNIQUE-- no BM or GI
Degraded by bleomycin hydrolase present most tissues except skin and lung
Pulmonary fibrosis is dose limiting in approximately 10%
- Stop Rx immediately
Skin
- desquamation, hyperpigmentation, and pruritic erythema

Clinical Uses

Broad range of squamous cell carcnomas, including --
- head and neck cancer
- tumors of cervix, esophagus, skin, vulva, and lung
Established against
- germ cell testicular cancer
- Hodgkin's disease, and non-Hodgkins L.
Many combo Rx due to lack of bone marrow toxicity

Miscellaneous Drugs

Cisplatin (Platinol^R, cis-DDP)

Structure

[fig] Structure of Cisplatin

Mechanism of action

Enters cells by passive diffusion
Aquated Cl- moieties react with N7 of guanine and other nucleophiles
Intrastrand (rapidly) and Interstrand (slowly) crosslinks in DNA
DNA - protein crosslinks
Cell-cycle nonspecific, but may be most active in G1

Adverse effects

Intractable, almost universal, nausea and vomiting
Anaphylactic-like reactions
Neurotoxicity
Myelosuppression
- mild compared to alkylating agents
- thrombocytopenia (by day 7-9)
- granulocytopenia (by day 17-19)
Nephrotoxicity is dose-limiting
- Dose related , cumulative, & irreversible
- Primarily affects proximal tubuls
  - tubular degeneration & loss of brush border
  - necrosis and mineralization of tubular epithelial cells
- Minimize
  - Hypersalination - forced infusion of hypertonic saline
  - Pre-Rx with thiol compounds may help (diethyldthiocarbamate (DDTC) or thiol sulfate)

Clinical Indications

Effective in --
- Testicular tumors
- Ovarian carcinoma
- Bladder tumors
- Head and Neck
- Breast cancer
- Lung cancer
- refractory non-Hodgkins lymphomas
Radiosensitizer -- optimal use of this ???

L-Asparaginase (Elspar^R)

Mechanism of action

Official name: L-asparagine amidohydrolase
Hydrolyzes asparagine to aspartic and ammonia
L-asparagine synthetase low in many malignant cells and must scavenge ASP from ECF

Adverse effects

Major problem: Antigenicity of enzyme -- allergic reactions
- experimenting with lipsomes and other means of delivery to decrease this
Inhibition of protein synthesis
Coagulation defect
- decreased clotting factors
Hepatotoxicity -- fatty metamorphosis
Anorexia, nausea, vomiting

Clinical Indications

Very narrow spectrum
Almost exclusively used to treat
- Acute lymphoblastic leukemia
Used in combination with vincristine and prednisone
May be useful in other T-cell or null-cell leukemias and lymphomas
NOT effective for solid tumors

Tamoxifen citrate (Nolvadex^R)

Antiestrogen
Estrogen dependent disseminated mammary gland cancer
Mild bone marrow suppression (anemia, leukopenia, anemia)
Tumor rash
Tumor pain

Corticosteroids, e.g., Prednisone

Adverse effects

Iatrogenic adrenal hypocorticism
Gastric ulcer, osteoporosis, increased susceptibility to infection
Polydipsia and polyuria

Clinical indications

Lymphoreticular neoplasms, brain tumors
Secondary complications of cancer -- mood elevation, stimulate appetite, decrease reaction to dying cells

References

Many - see textbook chapter by Coppoc in Adams, Veterinary Pharmacology, Iowa State Press, Ames

Many images in this text are redrawn from

Important source: Medical Oncology, 2nd Ed., Calabresi & Schein, et. al., McGraw Hill, 1993
Shackney, et al. Chapter 4 in Calabresi & Schein, '93

| Drug Groups | | top |
Gordon L. Coppoc, DVM, PhD
Professor of Veterinary Pharmacology
Head, Department of Basic Medical Sciences
School of Veterinary Medicine
Purdue University
West Lafayette, IN 47907-1246
Tel: 317-494-8633Fax: 317-494-0781
Email: coppoc@vet.purdue.edu

Last modified
9:22 AM on 4/24/96
GLC

CHEMOTHERAPY OF NEOPLASTIC DISEASES Outline, VPH 445

Topics

Overview

Factors determining therapeutic goals

Cancer Biology

Topics

Therapeutic problem

Tumor growth

Cell Kill is First Order

Sources of Heterogeneity in Tumors

Heterogeneity -- Pharmacokinetic

Heterogeneity -- Kinetic

Heterogeneity -- Genetic -- Resistance Mechanisms

Treatment Modalities

Toxicities Frequently Observed

Tissues / responses

Toxicities Related to Specific Drugs

Drugs

Categories

Nucleic Acid Nomenclature

Antimetabolites

Group Characteristics

Methotrexate

Structure

Mechanism of action

Adverse effects

Clinical Uses

Flurouracil, (5-FU)

Structure

Mechanism of action

5-FU: Biotransformation

Adverse effects

Effect of route and schedule on adverse effects

Effect of peak 5-FU concentration

Other adverse effects

Clinical Use of 5-FU

Alkylating Agents

Mechanism of action

Adverse effects of alkylating agents

Tumor resistance

Clinical Uses

Cyclosphosphamide

Structure

Mechanism of action

Clinical Pharmacology

Adverse effects

Sterile necrotizing hemorrhagic cystitis

Mesna for Px & Rx of Cystitis

Clinical Applications

Natural Products

Vinca Alkaloids

Mechanism of action

Adverse effects

Uses

Antitumor Antibiotics

General characteristics

Doxorubicin HCl (AdriamycinR)

Mechanism of action

Resistance

Adverse effects

Clinical Indications

Dexrazoxane

Bleomycin

Mechanism of action

Adverse effects

Clinical Uses

Miscellaneous Drugs

Cisplatin (PlatinolR, cis-DDP)

Structure

Mechanism of action

Adverse effects

Clinical Indications

L-Asparaginase (ElsparR)

Mechanism of action

Adverse effects

Clinical Indications

Tamoxifen citrate (NolvadexR)

Corticosteroids, e.g., Prednisone

Adverse effects

Clinical indications

CHEMOTHERAPY OF NEOPLASTIC DISEASES
Outline, VPH 445

Doxorubicin HCl (Adriamycin^R)

Cisplatin (Platinol^R, cis-DDP)

L-Asparaginase (Elspar^R)

Tamoxifen citrate (Nolvadex^R)