ANTI CANCER

Characteristics of cancer

1. • Uncontrolled proliferation (autonomous)

2. • Dedifferentiation and loss of function

3. • Tissue invasiveness-metastasis

FOUR Differences between cancer and infection

1. Infections Involve a Biologically Foreign Microbe

   • Infections are caused by external pathogens (bacteria, viruses, fungi, etc.) that are not part of the host.

2. Pathogen Metabolism Differs from Host Cells

   • Microbes have distinct metabolic pathways, making them easier to target selectively.

3. Selective Action of Chemotherapeutic Agents

   • Antimicrobials can often kill/inhibit microbes without damaging host cells due to this metabolic difference.

   • In contrast, anticancer drugs may also affect normal dividing cells (e.g. hair follicles, GI lining).

4. Host Immune System Aids in Defense

   • In infections, the body mounts a strong immune response using:

     • Antibodies

     • Phagocytosis

   • Cancer often evades or suppresses the immune response, making defense more difficult.

Factors influencing tumor genesis

1. Gene Mutations

   • Core driver of cancer development.

   • Includes activation of oncogenes and inactivation of tumor suppressor genes.

   • These mutations disrupt normal cell cycle control and promote uncontrolled growth.

2. Hormonal Action

   • Certain hormones (e.g. estrogen, testosterone) can promote growth of hormone-sensitive tumors like breast or prostate cancer.

   • Hormones can stimulate proliferation of cells, increasing the chance of mutation.

3. Co-Carcinogens

   • These are substances that enhance the effect of carcinogens but aren’t carcinogenic on their own.

   • They act by promoting inflammation or interfering with DNA repair mechanisms.

4. Tumor Promoter Effects

   • Tumor promoters are agents that stimulate cell proliferation after the initial genetic mutation.

   • They do not cause DNA damage themselves but enhance tumor development by increasing the proliferation of mutated cells.

• Proto-oncogenes:

  • Normal genes involved in cell growth and division.

  • When mutated, they become oncogenes.

• Oncogenes:

  • Mutated proto-oncogenes that promote uncontrolled cell division and survival.

  • Gain-of-function mutations — only one allele needs to be mutated for effect.

• Tumor Suppressor Genes:

  • Genes that inhibit cell growth and promote DNA repair or apoptosis.

  • Loss-of-function in both alleles leads to cancer progression (e.g., TP53, RB).

Types of Cancer chemotherapy

1. Curative Chemotherapy

   • Aimed at complete eradication of the cancer.

   • Most effective in cancers with high chemosensitivity.

   • Examples:

     • Testicular cancer

     • Lymphomas (e.g., Hodgkin and non-Hodgkin)

     • Leukaemias (especially acute types)

2. Adjuvant Chemotherapy

   • Given after surgery or radiation to eliminate micrometastases and reduce relapse risk.

   • Improves long-term survival.

   • Examples:

     • Breast cancer

     • Colon and rectal cancers

3. Multimodal (Combined-Modality) Therapy

   • Combines chemotherapy with surgery and/or radiation.

   • Used when cancer requires different treatment strategies for local and systemic control.

   • Examples:

     • Head and neck tumors

     • Lung cancer

     • Cervical and esophageal cancer

     • Sarcomas

     • Pediatric solid tumors

4. Emerging/Advanced Approaches

   • Involves novel therapies alongside traditional chemo:

     • Genetic therapy – targeting specific mutations.

     • Immunotherapy – manipulating immune response to attack cancer (e.g. checkpoint inhibitors).

     • Angiogenesis inhibition – blocking blood supply to tumors (e.g., bevacizumab).

     • Hematopoiesis stimulation – using agents like G-CSF to support bone marrow during chemo.

Uses of chemotherapeutic agents

1. Cytotoxic Anti-Tumor Therapy

   • Used to kill or inhibit the proliferation of cancer cells.

   • Examples: Methotrexate, Cyclophosphamide, Doxorubicin.

2. Immunosuppressive Therapy

   • Used to suppress abnormal immune responses in:

     • Autoimmune diseases (e.g., Rheumatoid Arthritis, Lupus)

     • Organ transplantation (to prevent rejection)

   • Examples: Azathioprine, Methotrexate, Cyclosporine.

3. Treatment of Sickle Cell Anemia

   • Some agents like Hydroxyurea increase fetal hemoglobin (HbF) levels, reducing sickling.

4. Psoriasis

   • Cytotoxic/immunosuppressive drugs reduce abnormal skin cell proliferation.

   • Example: Methotrexate, Cyclosporine.

5. Anti-Infective Chemotherapy

   • Includes antibiotics, antivirals, antifungals, and antiparasitics.

   • Targets pathogens selectively without harming host cells.

MOA of chemotherapeutic agents (6)

1. DNA Interaction & Damage

   • Direct interaction with DNA: Causes cross-linking, strand breaks, or interference with replication.

     • Example: Alkylating agents like cyclophosphamide.

   • Irreparable DNA damage: Triggers apoptosis in rapidly dividing cells.

     • Example: Cisplatin.

2. Inhibition of Genetic Material Synthesis

   • Blocks DNA or RNA synthesis, especially in dividing cells.

     • Example: Antimetabolites like methotrexate (inhibits dihydrofolate reductase) or 5-FU.

3. Anti-Proliferative Action

   • Targets mitosis or cell division machinery, halting proliferation.

     • Example: Paclitaxel (stabilizes microtubules), vincristine (prevents microtubule formation).

4. Immune Modulation

   • Enhances tumor-killing immune cells:

     • Example: Interleukin-2 (IL-2) stimulates proliferation of cytotoxic T cells and NK cells.

5. Kinase Inhibition

   • Inhibits tyrosine kinases that send growth signals in cancer cells.

     • Example: Imatinib – a tyrosine kinase inhibitor used in CML (targets BCR-ABL fusion protein).

     • Tyrosine kinases are enzymes that signal cell growth and survival.

6. Monoclonal Antibodies

   • Specifically target tumor antigens, leading to direct killing or immune-mediated destruction.

     • Examples:

       • Rituximab – targets CD20 on B-cells

       • Trastuzumab – targets HER2/neu in breast cancer

cell cycle

Cell cycle

• S phase - DNA synthesis

• G 2 phase - pre-mitotic interval

• M phase - mitosis

• G 1 phase - period between mitosis and DNA

synthesis

• Go phase - resting phase

Positive regulators of the cell cycle

• Cyclins

• Cyclic dependent kinases

Negative regulators of cell cycle

• P 53 protein

• Rb protein

• Cdk inhibitors

Chemotherapeutic regimen

• Combination therapy - synergism

• Drug interaction and toxicity

• Use drug with non overlapping mechanism of resistance and toxicity

• Maximum dose and dose interval

Survival tumor cells is mainly due to

• Loss of p53 suppressor oncogene, loss of apoptosis

• Over expression of bcl-2 oncogene that causes cell proliferation

Relationship of anti tumor drugs to cell cycle

Drug Class	Phase of Cell Cycle Affected	Examples	Mechanism
Phase Non-Specific	Active in all phases including G0	Alkylating agents, Nitrosoureas, Antibiotics (e.g. doxorubicin), Procarbazine, Cisplatin, Dacarbazine	Damage DNA regardless of the cell’s position in the cycle
S Phase Specific	DNA synthesis	Cytosine arabinoside, Hydroxyurea	Inhibit DNA synthesis or cause faulty DNA incorporation
S Phase Specific (Self-limiting)	S phase but with limited duration of activity	Methotrexate, 6-Mercaptopurine	Inhibit nucleotide synthesis → interfere with DNA replication
M Phase Specific	Mitosis	Vincristine, Vinblastine, Paclitaxel	Inhibit mitotic spindle formation (microtubule inhibitors)

🔬 Key Points

• S phase is highly sensitive to drugs because of active DNA synthesis — thus toxicity (e.g., bone marrow suppression) is often greatest here.

• M phase drugs (like vinca alkaloids and taxanes) prevent proper chromosome segregation → cell division arrest.

• Phase non-specific drugs are useful for killing both dividing and resting cancer cells.

GIVE EXAMPLES OF CELL CYCLE NON SPECIFIC CANCER DRUGS

• Alkylating agents -

Nitrogen mustards -

• mechlorethamine

• cyclophosphamide,

• melphalan,

• chlorambucil

• Ethylenimines -

• triethylenethiophosphoramide(Thio-TEPA)

• Methylhydrazine derivatives-

• procarbazine

• Triazenes

• dacarbazine

• Nitrosoureas -

• carmustine,

• bendamustine

• Platinum coordination complexes -

• cisplatin

• carboplatin

• oxaliplatin

• Antibiotics - dactinomycin, daunorubicin, doxorubicin, plicamycin, mitomycin

GIVE EXAMPLES OF CELL CYCLE SPECIFIC CANCER DRUGS

These drugs act only when cells are in specific phases of the cell cycle, so they are most effective against rapidly dividing cells.

Drug Class	Examples	Phase of Cell Cycle Affected	Mechanism of Action
Antimetabolites	Cytarabine, 5-Fluorouracil (5-FU), 6-Mercaptopurine (6-MP)	S phase	Inhibit DNA synthesis by mimicking normal nucleotides
Peptide Antibiotics	Bleomycin	G2 phase	Causes oxidative damage to DNA, mainly before mitosis
Podophyllotoxins	Etoposide, Teniposide	G2/phase	Inhibit topoisomerase II → DNA strand breaks
Plant Alkaloids	Vincristine, Vinblastine, Vinorelbine	M phase	Inhibit microtubule assembly → block mitotic spindle
Taxanes	Paclitaxel Docetaxel Cabazitaxel	M phase	Stabilizes microtubules → prevents their disassembly

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💡 High-Yield Tip:

• These drugs won’t work well on non-dividing (G0) cells.

• Combining cell cycle-specific with non-specific agents helps target a broader range of tumor cells.

Alkylating agents

• Cyclophosphamide

• Meclorethamine

• Melphalan

• Chlorambucil

• Ifosfamide

• Thiotepa

• Busulpan

MOA of alkylating agents

• Transfer alkyl group to various cellular constituents

• Leads to cell death

• Resistance by repairing of DNA

Nitrosoureas examples

• BCNU - Carmustine

• CCNU - Lomustine

• Methyl - CCNU -semustine

• Methyl - CCNU -semustine

Other than alkylating agents other anticancer drugs

• Antimetabolites

• Antibiotic and

• Vinca alkaloid

Anti tumor antibiotics

• Actinomycin D

• Dactinomycin

• Daunorubicin, Doxorubicin, Idarubicin

• Bleomycins

What are antimetabolites

• Antimetabolites are drugs that interfere with the metabolism of rapidly dividing cells, especially cancer cells.

• Cancer cells grow and divide faster than normal cells, so they rely more heavily on certain metabolic pathways — this makes them more vulnerable to these drugs.

Antimetabolite drugs are classified as

Folic acid analogs

Purine analogs

Pyrimidine analogs

MOA

• Act on nucleotide and nucleic acid synthesis

🔬 Mechanism of Action of Antimetabolites

Antimetabolites are structural analogs of purines, pyrimidines, or folic acid — all of which are essential for DNA and RNA synthesis. They work in three main ways:

1. Inhibit synthesis of nucleotides

They block enzymes that are essential for making purine or pyrimidine nucleotides (the building blocks of DNA/RNA).

Examples:

• Methotrexate inhibits dihydrofolate reductase (DHFR) → ↓ tetrahydrofolate → ↓ purine & thymidylate synthesis

• 5-Fluorouracil (5-FU) inhibits thymidylate synthase → ↓ dTMP → impaired DNA synthesis

2. Mimic nucleotides and get incorporated into DNA/RNA

These drugs look like real nucleotides, so cells mistakenly incorporate them into DNA or RNA during synthesis.
This leads to:

• Faulty DNA/RNA

• Chain termination

• Mutation or apoptosis

Examples:

• 6-mercaptopurine and 6-thioguanine → incorporated into DNA/RNA

• Cytarabine → incorporated into DNA → chain termination

3. Trap enzymes in inactive complexes

Some antimetabolites bind to enzymes in a way that traps them in inactive or toxic forms, halting the reaction and damaging the cell.

Example:

• 5-FU forms a complex with thymidylate synthase + folate → irreversible inhibition

🎯 Net Effect:

• ↓ DNA/RNA synthesis

• ↓ Cell replication

• ☠ Death of rapidly dividing cells (like cancer cells)

Folic acid analogues

• Methotrexate

• Pemetrexed

• Raltitrexed

• Lometrexol

• Trimetrexate

• Pralatrexate

Methotrexate - MOA

• Structurally similar to folic acid, it competitively inhibits the enzyme dihydrofolate reductase (DHFR).

• DHFR normally converts dihydrofolate (DHF) to tetrahydrofolate (THF), which is essential for:

  • Thymidylate synthesis (→ DNA)

  • Purine nucleotide synthesis (→ DNA and RNA)

  • Amino acid synthesis (e.g., serine, methionine)

• Result: Impaired DNA, RNA, and protein synthesis, especially in rapidly dividing cells.

Key Binding Property:

• Methotrexate binds extremely tightly to DHFR, particularly at pH 6, with little to no dissociation, making it a potent inhibitor.

Methotrexate Resistance Mechanisms

1. ↓ Drug Transport into the Cell

   • Due to decreased expression or mutation of the folate transporter (RFC1), which normally allows methotrexate to enter cells.

2. Altered Dihydrofolate Reductase (DHFR)

   • Mutations in the DHFR enzyme reduce its binding affinity for methotrexate.

3. ↑ DHFR Production

   • Gene amplification leads to overproduction of DHFR enzyme.

   • This overwhelms the inhibitory effect of methotrexate.

   • Results in increased DHFR mRNA and protein levels.

4. ↓ Polyglutamate Formation

   • Methotrexate is normally polyglutamated inside cells to enhance retention and activity.

   • Decreased polyglutamate formation → less drug retained in the cell → reduced efficacy.

PK of methotrexate

• PO or IV or IM or INTRATHECALLY

Well distributed into body cavities

50% PPB

metabolised partially

• 90% of oral dose excreted in urine within 12 hours

RETAINED AS POLYGLUTAMATE FOR WEEKS IN THE KIDNEY AND MONTHS IN THE LIVER

• Serum levels proportional to dose as long as serum levels and hydration status are adequate

Toxicity of methotrexate

ADRS

* BM: Myelosupression,thrombocytopenia

* Liver: Fibrosis, cirrhosis

* GIT: Nausea,vomiting,diarrhoea,mucositis, stomatitis,desquamation

* Skin: Erythema,rash,urticaria,alopecia, dermatitis

* Resp:Interstitial pneumonitis

* CNS: Meningismus,headache,seizure, coma

* Genital:Defective oogenesis,spermatogenesis

* Teratogenicity and abortions

* High dose:Nephrotoxicity

Use of methotrexate in neoplasia

• Choriocarcinoma

• ALL in children

• Meningeal leukaemia, lymphoma

• Burkitt's lymphoma,NHL, Ca breast, head & neck

• AML

• HDM-L

• Osteosarcoma

Non neoplastic indications of methotrexate

* Psoriasis

* Refractory RA

* Steroid resistant asthma

* Crohn's disease

* Wegener's granulomatosis

* Glomerulonephritis

* Dermatomyositis

* Immunosuppressive agent

* Abortifacient

Toxicity of methotrexate to normal cells is reduced by

1. Leucovorin rescue- administration of :

N10-formyl-tetrahydrofolic acid / folinic acid / citrovorum factor / leucovorin.

IT IS CONVERTED TO 5 , 10 methylene tetra hydrofolate→ bypassing the enzyme

*IT DOES NOT PREVENT NEUROTOXICITY

2. Alkalanisation of urine can also reduce methotrexate toxicity.

3. Administration of GLUCARPIDASE in extreme cases. glucarpidase is a methotrexate cleaving agent.

Methotrexate should not be administered with

NSAIDs like aspirin

Penicillins

cephalosporins

THEY MAY DECREASE RENAL EXCRETION OF METHOTREXATE AND RESULT IN TOXICITY.

PE

Purine antagonists

- 6-thiopurines

• 6-Mercaptopurine

• - 6-Thioguanine

•

Purine analogues / antagonists

Classic purine analogues

• Thiopurines

• 6 Mercaptopurine

• 6 Thioguanine

others - Fancy Cool Chemo People Need Purines

• Pentostatin

• Fludarabine PO4

• Cladribine

• Clofarabine

' nelarabine

Mercaptopurine MOA

• Metabolised by hypoxanthine guanine phosphoribosyl transferase (HGPRT) to the nucleotide form 6- thioinosinic acid (6-Tl) / Thioinosine monophosphate (TIMP)

• TIMP interferes with de novo purine synthesis by inhibiting a number of enzymes -

  • It inhibits amidophosphoribosyltransferase (also called PRPP amidotransferase), which is the rate-limiting enzyme in the purine synthesis pathway.

  • It also interferes with the conversion of IMP to AMP and GMP by inhibiting:

    • IMP dehydrogenase

    • Adenylosuccinate synthetase

also gets incorporated into DNA and RNA, leading to:

• Inhibition of DNA and RNA synthesis

• Cytotoxicity in rapidly dividing cells

• 6-thioguanalic acid and 6- methylmercaptopurineribotide are also formed from 6-MP may also be active

MOA of Thioguanine

• Inhibits several enzymes in the purine nucleotide pathway

• May cause metabolic lesions

• - inhibition of purine nucleotide interconversion

• - decreases intracellular guanine nucleotide thus inhibition of glycoprotein synthesis

• - interference with formation of DNA and RNA

• - incorporation of purine thiols in DNA and RNA

• - synergy of 6- MP with cytarabine

PK of 6- mecaptopurine and 6-thioguanine

• 6-MP and 6-TG are both given PO

• Excretion is mainly in urine

• 6-MP is metabolised by xanthine oxidase and converted to an inactive metabolite 6-thiouric acid (oxidation)

• 6-TG is metabolised by the same enzyme following deamination

Allopurinol use in chemotherapy

ALLOPURINOL IS USED IN CHEMOTHERAPY IN HAEMATOLOGICAL CANCERS TO PREVENT TUMOR LYSIS INDUCED HYPERURICEMIA.

• Allopurinol prevents hyperuricaemia by blocking purine oxidation(XANTHINE OXIDASE INHIBITOR) allowing excretion of cellular purines that are relatively more soluble that uric acid

•OTHER - Prevents nephrolithiasis and acute gout

WHAT SHOULD BE DONE WHEN CO ADMINISTERING BOTH ALLOPURINOL AND 6- MECAPTOPURINE?

• Concomitant use of 6-MP and allopurinol results in excessive toxicity of 6-MP thus dose reduction of 6-MP by 25-30% or 1/4th of the original dose

• This does not occur with 6-TG

HOW DOES RESISTANCE TO 6-MP OR 6-TG DEVELOP?

• Decrease in hypoxanthine-purine phosphoribosyl transferase activity

~ HGPRTase is required to convert these prodrugs into their active nucleotide forms.

Without activation, the drugs have no chemotherapeutic effect.

Uses of 6-MP and 6-TG

• Childhood acute leukaemias.

• Analogue of 6-MP - azathioprine is used as immunosuppressant

Fludarabine phosphate MOA

• Interferes with DNA synthesis through inhibition of DNA polymerase and ribonucleotide reductase.

Administration of fludarabine phosphate

Given parenterally and excreted in urine

Clinical use of fludarabine phosphate

Used in the treatment of lymphoproliferative disorders

DOC - CLL

ADRS of fludarabine phosphate

• Dose limiting myelosuppression

Cladribine - MOA

• Cause DNA strand breaks by interfering with DNA repair

• Use in treatment of hairy cell leukemia

• Myelosuppresant

Cladribine - clinical use

Use in treatment of hairy cell leukemia - DOC

• Myelosuppresant

Pyrimidine antagonists

• Fluorouracil

• Capecitabine

• Cytarabine

• Gemcitabine

Fluorouracil MOA

5 - FU is a prodrug.

• 5-FU is converted in the body into active nucleotide forms by deoxyuridine monophosphate.

• One form, FdUMP( 5 fluoro-2-deoxycytidine- 5'phosphate), FdUMP competes with dUMP (the natural substrate) for binding to thymidylate synthase and binds to and inhibits thymidylate synthase, blocking DNA synthesis.

• Another form, FUTP(Fluorouridine triphosphate), gets incorporated into RNA, disrupting RNA function.

• These effects lead to cell death → that’s how 5-FU is cytotoxic.

Fluorouracil - PK

• ADMIN -

  IV

  Topically in the case of skin cancer

  Erratic bioavailability PO

  DISTRIBUTION -

  The drug penetrates will into tissues including CNS

  METABOLISM -

  Rapidly metabolised in the liver, kidney, lungs and converted to fluoro -beta - alanine → EXCRETED in urine.

• Short metabolic half-life

— can increase the rate of catabolism and decrease bioavailability of 5-FU

elevated levels of Dihydropyrimidine dehydrogenase .

Varies from individual to individual

Pts with Dihydropyrimidine dehydrogenase deificiency may experience severe toxicity-

• pancytopenia

• mucositis

• life threatening diarrhea

5-FU clinical use

Topical for skin cancer

Systemically for adenocarcinoma

ADRS of 5-FU

Myelosuppression

mucositis

Capecitabine is a

• Fluoropyrimidine carbamate prodrug converted to 5-FU

Capecitabine - MOA

• Given orally

It is hydrolysed to 5 -FU as the last enzymatic step. It is catalysed by thymidine phosphorylase an enzyme that is primarily concentrated primarily in tumors

Capecitabine clinical use

Colorectal cancer

Metastatic breast cancer

Cytarabine is specific to what phase in the cell cycle

• S- phase specific antimetabolite

• Metabolite inhibits DNA polymerase

Cytarabine PK

• Admin - IV

• NOT ORALLY - due to deamination to noncytotoxic ara-U by cytidine deaminase in the intestinal mucosa and liver.

Distributes throughout the body EXCEPT THE CNS → THEREFORE IT MAY BE INJECTED INTRATHECALLY

Metabolised - undergoes extensiive oxidative deamination in the body to

ara-U - pharmacologically inactive.

Excretion - Both cytarabine and ara-U are excreted in urine.

Cytarabine clinical use

AML

Gemcitabine clinical use

• treatment of non-small cell lung cancer

• pancreatic cancer

• Myelosuppresant

Gemcitabine PK

IV administration

is deaminated to difluorodeoxyuridine - noncytotoxic

excreted in urine.

Vinca alkaloids are derived from

• Part of the natural product cancer chemotherapy drugs

• Derived from the Madagascar periwinkle plant, Catharanthus roseus (formerly called Vinca rosea).

• Include:

i. Vincristine ii. Vinblastine iii. Vinorelbine

vinca alkaloids includes

Include:

i. Vincristine

ii. Vinblastine

iii. Vinorelbine

MOA

MITOTIC SPINDLE INHIBITORS

• Inhibit tubulin polymerization→ disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle.

• Results in mitotic arrest in metaphase→halts cell division, leading to cell death.

Microtubules are found in high concentrations in the brain - disruption causes neurotoxicity

Are vinca alkaloids cell cycle specific

specific to the M phase

inhibit mitotic spindle formation → preventing cell division

PK OF VINCA ALKALOIDS

• Aministration - IV

  • VINCA ALKALOIDS SHOULD NOT BE ADMINISTERED INTRATHECALLY → IN CAN RESULT IN DEATH.

• Extensively metabolized in the liver

• Metabolites are excreted in bile

• < 15% is going in the urine unchanged

• Dose adjustment required in patients with hepatic dysfunction

• Half lives:

Vincristine= 20 hrs

Vinblastine= 23 hrs

Vinorelbine=24 hrs

1. Vinblastine

Is given intravenously

• Avoid subcutaneous extravasation → painful irritation and ulceration.

Therapeutic uses of vinblastin

i. Testicular tumors (administered with bleomycin and cisplastin)

ii. Hodgkin's lymphoma

iii. Kaposi sarcoma

iv. Neuroblastoma

v. Langerhans cell histiocytosis

vi. Carcinoma of the breast

vii. Choriocarcinoma.

Clinical toxicities

• Leukopenia- nadir (lowest WBC count) within 7-10 days, with recovery in another 7 days.

• VBL IS A POTENT MYELOSUPPRESSANT.

• Mild neurological manifestations.

• Nausea, vomiting, anorexia & diarrhea.

• Alopecia, stomatitis & dermatitis.

• Extravasation → cellulitis.

2. Vincristine

ADMINISTRATION AND DOSAGE

Is given IV

dose - • Dose : 2mg/m2 in children : 1.4mg/m2 in adults

• Better tolerated by children than adults, who may experience severe, progressive neurological toxicity.

• Given at weekly intervals.

Therapeutic uses

• Childhood leukemia - ALL

• Pediatric solid tumors- Wilms tumor, neuroblastoma & rhabdomyosarcoma

Hodgkin’s lymphoma

• Non Hodgkin’s lymphoma

Clinical toxicities of vincristine

• Mostly neurological- sensory & motor disturbances → NEUROTOXIC - PERIPHERAL NEUROPATHY

• Severe constipation

• Alopecia in 20% (reversible without cessation of therapy)

• Thrombocytopenia, anemia.

• Myelosuppression is much less than that caused by Vinblastine. (VINOCRISTINE IS BONE MARROW SPARING)

• Extravasation → cellulitis and phlebitis

3. Vinorelbine administration and dosage

Administered in normal saline as an iv infusion over 10 minutes

• Dose: 25- 30 mg/m2 weekly

Indications of vinorelbine

Useful in:

i. Non-small cell lung cancer

ii. Breast cancer

Clinical toxicities of vinorelbine

Has an intermediate toxicity profile

• Primary toxicity is granulocytopenia

• Allergic reactions

• Mild changes in liver enzymes

Advantage of vinorelbine compared to other vinca alkaloids

Less neurotoxicity than other vinca alkaloids

Antitumor antibiotics are produced by

• Are produced by Streptomyces strains

• Bind to DNA within tumor cells and interfere with replication

MOA of antitumor antibiotics

• Bind to DNA within tumor cells and interfere with replication

Antitumor antibiotics includes

Include:

a. Anthracyclines

b. Bleomycin

c. Mitomycin

d. Mitoxantrone

1. Anthracyclines are isolated from

• Are isolated from Streptomyces peucetius var caesius.

• Examples:

a. Doxorubicin

b. Daunorubicin

c. Idarubicin

d. Epirubicin

Anthracyclines include

a. Doxorubicin

b. Daunorubicin

c. Idarubicin

d. Epirubicin

Are antitumor antibiotics cell cycle specific or non specific

ALL CELL CYCLE NON SPECIFIC EXCEPT BLEOMYCIN

Pk of anthracyclines

• Given IV

• Extensive liver metabolism to an active hydroxylated metabolite & an inactive aglycone metabolite.

• Up to 50% is eliminated in the faeces.

• Dose reduction required in liver dysfunction.

• Usually given every 3 weeks.

MOA of cytotoxic action of antitumor antibiotics (4)

1. Inhibition of topoisomerase lI

2. DNA intercalation, blocking synthesis of DNA & RNA.

3. Generation of semiquinone- and oxygen free radicals

4. Binding to cellular membranes to alter ion transport.

Daunorubicin use

• First agent in the class to be isolated

• Use- treatment of acute myeloid leukemia (AML).

Idaribicin

IDARUBICIN

• Semisynthetic analog of Daunorubicin

• More active than Daunorubicin in achieving remission and improving survival in AML.

DARUBICIN

• Semisynthetic analog of Daunorubicin

• More active than Daunorubicin in achieving remission and improving survival in AML.

DOXORUBICIN USE

• Solid tumors- breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung.

• Hematologic malignancies- acute lymphoblastic leukemia, multiple myeloma, Hodgkin's and non-Hodgkin's lymphomas.

• Childhood cancers- neuroblastoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma.

ADRs of anthracycline antibiotics

1. Myelosuppression- Dose limiting.

Neutropenia >>>>thrombocytopenia.

2. Mucositis- may also be dose-limiting.

3. "Radiation recall reaction" - erythema & desquamation of the skin at sites of prior radiation.

4. Cardiotoxicity: → Due to free oxygen radical damage to the myocardium

a. Acute- First 2-3 days & transient. Arrhythmias, pericarditis, myocarditis.

b. Chronic

- Dilated cardiomyopathy with heart failure

- Seen with cumulative dose >500-550mg/m2.

Cardiotoxicity of anthracycline antibiotics can be reduced by use of

Dexrazoxane → free radical scavenger

MITOMYCIN is isolated from

• Antibiotic isolated from Streptomyces caespitosus.

Mechanism of cytotoxic action of mitomycin

MITOMYCIN ACTS AS AN ALKYLATING AGENT

• Activated through enzyme-mediated reduction → generates an alkylating agent → cross-links DNA.

• Hypoxic tumor stem cells of solid tumors thus more sensitive to its cytotoxic effect as they exist in an environment conducive to reductive reactions.

Clinical uses of mitomycin

• Best drug to use in combination with radiation therapy to attack hypoxic tumor cells.

• Squamous cell cancer of the anus & cervix.

Breast, gastric & pancreatic cancer.

Intravesical treatment of superficial bladder cancer (no systemic toxicity).

ADRS of mitomycin

• Hemolytic uremic syndrome ~ rare

• Interstitial pneumonitis

• Myelosuppression

• Mucositis

GIT symptoms

BLEOMYCIN MOA

• Structure- Is a small peptide containing a DNA-binding & iron-binding domain.

Causes DNA strand breakage by oxidative process and free radical formation.

• Bleomycin forms a complex with Fe²⁺ (ferrous iron) and DNA.

• This complex gets oxidized to Fe³⁺, releasing electrons.

• The electrons react with O₂ to form superoxide and hydroxyl radicals (ROS).

• These ROS attack DNA, breaking phosphodiester bonds → causes:

  • Strand breaks

  • Chromosomal damage

IS BLEOMYCIN CELL CYCLE SPECIFIC OR NON SPECIFIC

Is cell cycle specific

• Causes accumulation of cells in the G2 phase.

BLEOMYCIN PK

• Given SC, IM or IV.

• instillation in the bladder for bladder ca.

Bleomycin is hydrolysed by bleomycin hydrolase to inactive metabolites. The enzyme is in low concentrations in the skin and lungs ~thus are major organs involved in toxicity.

• Excretion mainly via kidneys.

• Requires dose adjustment in renal failure.

BLEOMYCIN Clinical use

• Hodgkin's and non-Hodgkin's lymphomas,

• Germ cell tumors

• Head and neck cancer

• Squamous cell cancer of the skin, cervix & vulva

BLEOMYCIN ADRS

• Pneumonitis- dose-limiting. Risk increased with cumulative doses > 400 units.

• Pulmonary fibrosis

• Mucositis

• Alopecia

Hyperpigmentation of the hands

Hyperkeratosis

erythema

• Acute- allergy, fever, hypotension

myelosuppression is rare

Minimal myelosuppressive and immunosupressive

DACTINOMYCIN is also known as

actinomycin D

Crystalline antibiotic from streptomyces culture