CANCER CHEMOTHERAPY

2. Trimetrexate
Principles of Cancer Chemotherapy - antimalarial agent, also a potent inhibitor of DNHFR
Goal of treatment
A. Cure – eradication of every neoplastic cell
B. Palliation – alleviation of symptoms and avoidance of life 3. 6 – Mercaptopurine
threatening toxicity - the thiol analog of the purine hypoxanthine. It is converted
to the corresponding nucleotide – 6-thioinosinic acid 6 T-
Tumor susceptibility and the growth cycle IMP which inhibits the formation of adenine and guanine
4 Phases of the Cell Cycle from Inosinic monophosphate (IMP).
1. M phase – period of mitosis (cell division) - Fate: 6 MP is converted to thiouric acid in the liver (this
2. G1 phase – interval during which RNA, protein synthesis and reaction is catalyzed by xanthine oxidase)
cellular growth occurs
3. S phase – DNA synthesis
4. G2 phase – synthesis of cellular components required for
mitosis
5. Go- resting state where cell is not dividing

4. 6- Thioguanine (6 TG)
- MECH = converted to 6 –thioguanine 5 Phosphate (6-thio-
GMP) which replace guanine nucleotide and inhibit DNA
synthesis

5. Fluorouracil (5 FU) Inhibits thymidylate

2 Types of Cancer Chemotherapeutic Agents base on its effect on
cell cycle
1. Cell – cycle specific drugs – drugs that inhibit cell replication
during a phase of a cycle.
Example: Methotrexate – inhibits DNA synthesis during S-
phase(Antimetabolite)
Others: Bleomycin, Antibiotics, Vinca Alkaloids
- They are effective for Cancer with a high growth fraction (e.g –
hematologic cancers)
synthetase thus interferes DNA production
6. Floxuridine (FUDR or 5 FUDR)
- MECH= 5 FU is a pyrimidine analog. Interferes the
conversion of deoxyuridylic acid to thymidylic acid.
- 5 FU must be converted to 5 FdUMP-( 5 Fluorodeoxyuridine
monphosphate,) which competes with deoxyuridine
monophosphate for the enzyme thymidylate synthetase.
- 5 FU is metabolized in the liver to CO2 which is then
expired.

2. Cell-cycle non specific – agents that are active while the cancer
cells are dividing but whose action spans more than one phase
of the cycle as well as within Go.
• Example: Mechlorethamine, cisplatin, nitrosourceas
• they are effective for both high growth fraction as
well as low fraction malignancies e.g solid tumors

ANTI CANCER DRUG CLASSIFICATION:

I. ANTIMETHABOLITES
– are structural analogs of naturally occurring substances
– inhibits DNA synthesis. They are S-phase specific (except
5FU)
They act in 2 ways:
a. By incorporation into a metabolite pathway and
formation of a false metabolite
b. By inhibition of the catalytic function of an enzyme or
enzyme system

Antimetabolite
a) Folate antagonist : Methotrexate, Trimetrexate
b) Purine derivatives : Mercaptopurine ,Thioguanine
c) Pyrimidine derivative : Fluorouracil (5 FU), Floxuridine,
Cytarabine

1. Methotrexate
Mechanism of Action – competes with folic acid for the active
binding sites on dihydrofolate reductase (DHFR) enzyme

7. CYTARABINE ( CYTOSINE ARABINOSIDE, ARA –C)

Analog of 2 –deoxycytidine
• S- CYCLE SPECIFIC
• MECHANISM OF ACTION –an pyrimidine
antimetabolite ,phoshorylated to the active cytotoxic
nucleotide cytosine arbinase triphosphate, an
inhibitor of DNA polymerase
• Given parenterally ,not orally because it is
deaminated to a noncytotocic product in the intestinal
mucosa
• uses – is an imporatnt component for the treatment
of acute leukemias
• Toxicities – GIT irritation , myelosuppresion ,
neurotoxicity (cerebellar dysfunction and peripheral
neuritis)

II. ALKYLATING AGENTS –are cycle phase nonspecific

Pharmacokinetic:
- converted to polyglutamated metabolite which also
inhibits DHFR
- also converted to a 7-OH derivative by
hydroxylation – less water soluble – may lead to
crystalluria in acidic urine, and may cause renal
damage. Major route of elimination – kidneys.
• MECHANISM OF ACTION – form covalent bonds with nucleophilic
sites on nucleic acid, phosphate, amino acid and proteins
through the formation of carbonium ion which attack the N7
POSITION OF GUANINE
• THIS LEADS TO DNA MISREADING , ABNORMAL BASE PAIRING ,
DNA INTERSTRAND CROSS LINKING AND DNA STRAND
BREAKAGE
 • TOXICITY : adrenal insufficiency pulmonary fibrosis and
skin pigmentation

9. STREPTOZIN- has high affinity for beta cells of islet of

langerhans of pancreas

10. DACARBAZINE –used in treatment regimen in hodgkins

disease as part of the abvd regimen(adriamycin, bleomycin,
vinblastine,decarbazine)

III -Antibiotics – Binds to DNA by intercalation.

ALKYLATING AGENTS Inhibit DNA or RNA synthesis cycle phase non specific
A. NITROGEN MUSTARD :
1. MECHLORETHAMINE
2. CHLORAMBUCIL 1. Dactinonomycin - focus a complex with
3. CYCLOPHOSPHAMIDE (Actinomycin D) DNA involving selective
4. MEPHALAN binding to and
5. IFOSFAMIDE intercalation between
B. NITROSOUREAS the guanine-cytosine
1. LOMUSTINE segments
2. CARMUSTINE - Causes also single
3. STRETOZOCIN stranded breaks in DNA
C. TRIAZINES 2. Plicamycin(Mithramycin) – (Similar to Dactinomycin). It
DACARBAZINE comes from Streptomyces inhibits the synthesis of DNA
D. ALKYL SULFONATE : plicatus. dependent RNA synthesis
BUSULFAN - Toxic specific for
E. PLATINUM DERIVATIVE asteoclasts and lowers
CISPLATIN serum calcium
CARBOPLATIN
F. METHYLHYDRAZINE 3. Bleomycin Sulfate – derive - Binds with DNA to
PROCARBAZINE from S. Verticillus. produce single & double
stranded breaks
1. MECHLORETHAMINE - It is antitumor, anti
viral and anti bacterial. - DNA is cleaved at
• coverted spontaneously into a reactive cytotoxic product. It is a mixture of guanine-cytosine and
acts on all phase but most sensitive is G1 and S PHASE different copper guanine-thymine seq.
• CLINICAL USES : use in combination with other anti cancer chelating glycopeptide
agents in the MOPP regimen(Mechlorethamine, Oncovin or
Vincristine, Procarbazine, Prednisone

2. CYCLOPHOSPHAMIDE
• A nitrogen mustard that is biotransformed by the hepatic
cychrome p450 into hydroxylated intermediates :
phosphoramide , the active alkylating agent (anti- cancer)
and acrolein which can cause hemorrhagic cystitis
• TOXICITY : hemorrhagic cystitis (prevention of this is by
4. a. Doxorubicin - Are anthracycline antibiotics
vigorous hydration and the use of
(adriamycin)
mercaptoethanesulfonate (mesna))
b. Daunorubicin
-cardiac dysfunction, pulmonary toxicity
Mech. Of Action:
3. CHLORAMBUCIL – SLOWEST ACTING ALKYLATING AGENT
1. Intercalation in the DNA – the drug inserts between
adjacent base pairs and binds to sugar- PO4 backbone
4. IFOSFAMIDE – A DERIVATIVE OF CYCLOPHOSPHAMIDE of DNA, thus blocking DNA synthesis

5. CARMUSTINE (BCNU) AND LOMUSTINE (CCNU) 2. Binds to cell membrane and alters the function of
• ARE NITROSOUREAS WITH HIGH LIPOPHILICITY THAT transport process
FACILITATES CNS ENTRY 3. Generation of Oxygen radicals or superoxide
• USE –TREATMENT OF BRAIN TUMORS

6. CISPLATIN AND CARBOPLATIN

• Cisplatin is given intraveneously, cleared unchanged by
the kidney
• USE – component in the treatment regimen for testicular
carcinoma, cancers of the bladder, lung and ovary.
• TOXICITY : git distress ,mild hematoxicity ,but neurotoxic
(pheripheral neuritis and acoustic nerve damage )and
nephrotoxic . renal damage may be reduce by the use of
mannitol and forced hydration . 5. Mitomycin - comes from - Active most in cell cycle in
• Carboplatin is less nephrotoxic ,less likely to cause tinnitus Streptomyces late G and early S phase.
and hearing loss but has a greater myelosuppresant Calspitosus contains Potentiates cardiotoxic
actions quinone, a urethane and effect of Doxorubicin
an aziridine
7. PROCARBAZINE –
• MECH OF ACTION =a reactive agent that forms hydrogen IV – Plant derivatives
1. Vinca Alkaloids
peroxide ,which generates free radicals that cause dna
a. Vinblastine - Block mitosis in
strand scission Metaphase
b. Vincristine
• orally active, penetrates most tissues ,including csf. - Binds to Tubulin inhibit
Source: periwinkle plant (vinca
eliminated via hepatic metabolism assembly of
rose)
• USE= component of mopp regimen for the treatment of - Both cycle and phase microtubules thus the
failure of mitotic spindle
hodgkins disease specific Mitotic spindle
- cells in S phase are
• TOXICITY =myelosuppresant ,git irritation ,cns dysfunction, most sensitive
peripheral neuropathy and skin reactions . can cause a
disulfiram like reaction with ethanol , it is also
leukemogenic

8. BUSULFAN –AN ALKYL SULFONATE

• USE = treatment regimen for myelogenous leukemia
 2.
-
Epipodophylltoxins
Etoposide (VP-16) - Appears to arrest cells • Rifuximab = a monoconal antibody to a surface protien in
- Teniposide (VM-26) in G2 phase HodgKins lymphoma cells.
- Synthetic derivatives of - Cause dose dependent • Trastuzumab = is a monoclonal antibody to a surface protien
the extract of the break on DNA strands in breast cancers that overexpress the HER2 protien. Can cause
American mandrake
cardiac dysfunction, including CHF
plant - Probably act through Therapeutic Usefulness:
inhibition of DNA
topoisomerase II 1. Methotrexate ALL, chorio CA, BukKitts Lymphoma
in Children, breast, neck and head
3. Taxanes: Paclitaxel, - are spindle poisons but CA
docetaxel Given IV--- act differently from
Clinical use: used in vinca alkaloids. They 2. 6 Mercaptopurine ALL (acute Lymphoblastic Leukemia)
advanced breast and prevent microtubule
ovarian cancers disassembly into 3. 6 THioguanine Acute myelocytic leukemia
tubulin monomers
4. 5 Fu CA of colon, breast, ovarian,
• Toxicity:
pancreatic, gastric CA
- Paclitaxel: causes neutropenia, thrombocytopenia, a high
incidence of peripheral neuropathy and possible 5. Cytarabine Acute myclogenous leukemia.
hypersensitivity reactions during infusion.
- Docetaxel: neurotoxicity and BMS 6. Dactinomycin Wilm’s tumor, chorio CA, soft tissue
sarcomas
V – Miscellaneous Agent
7. Doxorubicin ALL, HodgKins, breast and Lung CA
Mechanism of Action
8. Daunorubicin AML
1. Amsacrine - cytotoxic, binds to DNA through 9. Bleomycin Testicular tumors (w) vinblastine
intercalation and has base specificity and cisplatin
on A-T pairs
10. Plicamycin Bone tumor
- more effective in cycling cells
11. Mechlorethamine HodgKin (MOPP regimen
2. 2. Asparaginase - Hydrolyzes blood asparaginase which Mechlorethamine, Oncovin,
(L- is necessary for growth and function Prednisone, Procarbazine)
Asparaginase) of cells, thus tumor cells are
deprived of this nutrient required for 12. Cyclophosphamide BurKitts and Breast CA lymphoma
protein synthesis.
13.Lomustine/Carmustine malignant glioma

14. Vincristine ALL, Wilms tumor, Ewings, Soft

tissues sarcoma and HodgKins

15. Vinblastine testicular CA, Hodgkin

16. Dacarbazine) malignant melanoma

Hodgkins (combine with
Doxorubicin)

17. Streptozocin Pancreatic cell carcinoma

18. Etoposide Oat cell carcinoma of lungs

Treatment Choices for Cancer responsive to Systemic Agents

1. Acute lymphocytic Induction: Combination Chemo
leukemia (ALL)
Adults: Vincristine, Prednisone,
For Remission: Daunorubicin,Asparagin
maintenance- ase
Methotrexare,
Vl – Hormones – mainly Palliative Thioguanine For children: w/o aspaginase
- Antagonize or lower concentration of normally occuring hormones
in hormone dependent tumors 2. Acute Myelocytic and Combination Chemo
1. Adrenocorticosteroids – useful in acute leukemia in children and myelomonocytic
leukemia Cytarabine Daunorubicin or
malignant lymphoma. idarubicin
2. Aminogluthethimide (cytadren)
- inhibits synthesis of adrenocorticosteroids 3. Chronic Myelocytic Hydroxyurea; alpha interferon
- when administered with hydrocortisone can effectively leukemia (Busulfan,
reduce estradiol levels
- useful in advanced carcinoma of the breast (estrogen- Mercaptopurine, thioguanine,
receptor(+) tumors cytarabine,plicamycin)
3. Mitotane(O,P –DDD) (Lysodren) 4. Chronic lymphocytic Chlorambucil+ Prednisone or
- Selectively attacks adrenocortical cells leukemia fludarabine
- use in palliative treatment of inoperable adrenocortical
carcinoma 5. Hairy cell Alpha interferon cladribine
4. Progestins– useful in the management of endometrical CA.
(Hydroxy Progesterone Megestrol) 6. HodgKins dis Combination Chemo (ABVD)
5. Estrogens – use to treat prostatic CA. (estradiol, (stages III & IV)
1. Doxorubicin (Adriamycin)
diethylstilbesterol) Combination Chemo
Estramustine – a nitrogen mustard linked to estradiol, use as a (MOPP) 2. Bleomycin
palliative treatment of advanced prostatic carcinoma.
6. Androgens - use to treat carcinoma of the breast in both 1. Mechlorethamine 3. Vinblastin
premenopausal and past menopausal women. (Testosterone 4. Dacabazine
fluoxymesterone) 2. Vincristine
7. Tamoxifen – antiestrogen – competes with estrogen for binding 3. Prednisone
with receptor
- use in CA of breast, estrogen(+) receptors 4. 4. Procarbazine
8. Gonadotropin – reduces circ. Gonadotropins and testosterone.
Effective in prostatic carcinoma. 7. Non HodgKins Combination Chemotheraphy
lymphoma
- Cyclophosphamide
VII- Aromatase Inhibitors:
Anastrozole and letrozole inhibit aromatase, the enzyme that catalyzes - Vincristine
the conversion of androstenedione (an androgenic precursor) to estrone
(an estrogenic hormone) - Doxorubicin
Uses: Advanced breast cancer
- Prednisone
Toxicity: Nausea, diarrhea, hot flashes, bone and back pain, dyspnea and
peripheral edema. 8.Multiple Myeloma Combination Chemotherapy

VIII- Monoclonal Antibodies: - Melaphalan + Prednisone or

1. Melaphalan
 2. Cyclophosphamide
3. Carmustine
4. Vincristine
5. Doxorubicin
6. Prednisone
9. Waldenstrom's Chlorabucil or Combination
Macroglobulinemia Chemotherapy
1.Cyclophosphamide
2. Vincristine
3. Prednisone
10. Polycythemia Vera Hydroxyurea
11. carcinoma of Lung Combination Chemotherapy
(small cell)
Cisplatin and etoposide
(palliative – Radiation)
12. Non-small cell Lung Advance – Cisplatin + Vinorelbine
CA
Localized – Cisplatin + Vinblastin
113. Carcinoma of the Combination Chemotherapy
head and neck
1. Cisplatin and 5 FU
14. Carcinoma of the Combination Chemotherapy
Esophagus
1. 5 FU
2. Cisplatin
15. Carcinoma of the Stomach – Etoposide: 5FU w/
Stomach and Pancreas leucovorin (ELF)
Pancreas – 5 FU or ELF
16. Carcinoma of the Colon - Fuorouracil + levamisole
colon (adjuvant) or w/ leucovorin
Rectum – 5FU w/ radiation therapy
(adjuvant)
17. Carcinoma of the Vinblastine
kidney
18.Carcinoma of the Combination Chemotherapy
bladder
1. Methotrexate
2.Vinblastine
3. Doxorubicin
4. Cisplatin
CMF regimen: Cyclophosphamide plus
19. Breast Carcinomamethotrexate& fluoouracil, or doxorubicin
(stages I &II) for methotrexate
CAF regimen: tamoxifen if hormone
receptor positive
20. Breast carcinoma - As above paclitaxel, plus
(stages III & IV) trastuzumab(if HER2 protein) w/ or
w/o aromatase inhibitors
Dose limiting adverse effects of Chemotherapetic agents
1. Methotrexate - Bone marrow suppression (BMS)
- oral and GI ulceration
- acute renal failure
- hepatotoxicity
2. 6 Mercaptopurine - BMS, oral and GI ulcers
3. 6 Thioguanine - BMS
4. 5 FU - BMS, oral and GI ulcers
dacryocystitis
5. Cytarabine - BMS, CNS toxicity
6. Dactinomycin - BMS, stomatitis, oral ulcers
7. Doxorubicin - BMS, cardiotoxicity
8. Bleomycin - Pneumonitis, pulmonary fibrosis
9. Plicamycin - BMS, hemorrhagic cystitis
10. Mitomycin - BMS, trombocytopenia, leukopenia
11. Mechlorethamine - BMS
12. Cyclohosphamide - BMS, hemorrhagic cystitis
13. Nitrosoureas - Thrombocytopenia, leukopenia
14. Vincristine - Peripheral neuropathy
15. Vinblastine - BMS
16. Progesterone - fluids retention, hypertension
17. Tamoxifen - nausea and vomiting
18. Estrogen - thromboembolic accidents
19. Busulfan - skin pigmentation, pulmonary
fibrosis, adrenal insuffiency
20. Cisplastin - Nephrotoxicity (renal toxicity) and
acoustic nerve dysfunction
21. Procarbazine - BMS, CNS depression
22. L-asparaginase - Allergic reactions, fever,
pancreatitis, thrombocytopenia
23. Etoposide BMS, allergic reaction
24. Fluoxmesterone - Cholestatic jaundice
Principles of Combination Therapy
1. Each drug should be active when used alone against the particular
cancer.
2. The drugs should have different mechanism of action.
3. Cross – resistance between drugs should be minimal.
4. The drugs should have different toxic effects.
Combination Chemotherapy
1. HodgKin's disease
a. MOPP regimen Mechlorethamine, Oncovin (vincristine),
Procarbazine, Prednisone
b. ABVD regimen, Adriamycin, (Doxorubicin) Bleomycin,
Vinblastine, Decarbazine
2. Non-Hodgkins Lymphoma
COP regimen – Cyclophosphamide, Oncovin, Prednisone
3. Testicular Cancer – PVB regime, Plationol, Vinblastine, Bleomycin
4. Breast Cancer
a. CMF regimen – Cyclohosphamide, Methotrexate, Fluorouracil
with or without Tamoxifen
b. CAF – in which Adriamycin(Doxorubicin) replaces Methotrexate
Additional Strategies for cancer Chemotherapy
1. Pulse therapy – involves intermittent treatment with very high
doses of an anti-cancer drug-are too toxic to be used continuously.
Intensive drug treatment is every 3-4 weeks.
This type of regimen is used in therapy of:
1. acute leukemia
2. testicular CA
3. Wilms tumor
2. Recruitment and Synchrony – the strategy of recruitment
involves initial use of CCNS drug to achieve a significant log kill,
which results in the recruitment into cell division of previously
resting cells in the GO phase. With subsequent administration of
CCS drug that is achieve against dividing cells.
Syncrony – example the use of vinca alkaloids to holds cancer
cell in the M phase and subsequent treatment of
another CCS drug such as the S-phase specific
Cytarabine which results in a greater killing effect
on the neoplastic cell population
3. Rescue Therapy – use to alleviate toxic effects of anticancer
drugs.
a. Leucovorin – bypasses the dihydrofolate steps
reductase in folic acid synthesis thus reducing toxicity
of antifolate agents.
b. Mercaptoethanosulfonate(mesna) - “Traps”
acrolein released from Cyclophosphamide thus
reducing hemorrhagic cystitis.
c. Dexrazoxane – a free radical “trapper” that protect
against cardiac toxicity due to anthracyclines
(doxorubicin)