1. General principles and classification

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).

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

Nitrosoureas

• BCNU - Carmustine

• CCNU - Lomustine

• Methyl - CCNU -semustine

• Methyl - CCNU -semustine

MOA of alkylating agents

• Transfer alkyl group to various cellular constituents

• Leads to cell death

• Resistance by repairing of DNA

Pharmacological effects of alkylating agents

• Direct vesicant

• Toxicity dose dependent on rapidly growing tissue - BM, GIT, Gonads

• IV nausea and vomiting within 30- 60 mins

• Emesis central and treated with 5HT receptor antagonists e.g ondansetron and granisetron

• SC injection tissue necrosis

• Cyclophosphamide no direct vesicant effect and has to be activated to active form by CYP

enzymes

• Activated by CYP

• Form active products including acrolein which cause haemorrhagic cystitis

• Bone marrow suppression dose related

• Cytopenias in 10- 28 days

• Greater cytopenias with DXT and other myelosuppresants

• Intermittent dosing to allow recovery

• Cyclophosphamide, chlorambucil, melphalan and busulphan used orally

• Used in combination with other classes of CX7

agents

Nitrosureas

• Non cross reactive with alkylating agents

• Highly lipid soluble thus use in brain tumours

• Alkylate DNA

• Procarbazine, dacarbazine, altrexamine,cisplatin, carboplatin act as alkylating agents

• Platinum compounds - cis and carboplatin has lower BM toxicity but causes nausea and vomiting and acoustic nerve dysfunction.

• Nephrotoxicity minised with hydration

• Cisplatin used majorly in genitourinary, testicular, ovarian and bladder cancer

Other than alkylating agents other anticancer drugs

• Antimetabolites

• Antibiotic and

• Vinca alkaloid

Anti tumor antibiotics

• Actinomycin D

• Dactinomycin

• Daunorubicin, Doxorubicin, Idarubicin

• Bleomycins

Actinomycin D

• Crystalline antibiotic from streptomyces culture

• Useful in childhood tumours and choriocarcinoma

• MOA - binds double helical DNA

• Inhibits rapidly proliferating cells and can produce alopecia and vesicant when extravasates

• IV >PO in efficacy

• Excreted in bile and urine

• Half life 36 hours

• Does not cross BBB

Actinomycin D Uses

• Rhadomyosarcoma and Wilm's tumour in children

• Ewing's tumour

• Testicular tumours

• Non- hogkins

• immunosuppresant

Toxicities of Actinomycin D

• Nausea, anorexia and vomiting

• Pancytopenia

• Proctitis, cheilitis, oral mucosa ulceration

• Alopecia, erythema

Daunorubicin ,doxorubicin, idarubicin

• Anthracyclines

• rdSource streptomyces peucetius

• Idarubicin synthetic

• Dauno and idarubicin -acute leukaemias

• Doxorbicin - solid tumours

• Can cause irreversible cardiomyopathy

• Structure - tetracycline ring + sugar

• MOA - intercalate with DNA

• Mutagenic and carcinogenic

• Given IV

• Newer analogues -Valrubicin

• Related agent mitoxantrone - use for acute nonlymphocytic leukaemia

:

Anthracyclines Overview

• Examples:

  • Daunorubicin

  • Doxorubicin

  • Idarubicin (synthetic)

• Source:

  • Streptomyces peucetius (natural source for daunorubicin and doxorubicin)

  • Idarubicin is synthetic.

• Structure:

  • Tetracycline ring with a sugar component.

  • This structure allows them to intercalate with DNA (insert between base pairs).

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Mechanism of Action (MOA)

• Intercalation: The drug inserts itself between DNA base pairs, disrupting DNA replication and transcription.

• Free Radical Formation: Anthracyclines also generate free radicals, leading to further DNA damage.

• Inhibition of Topoisomerase II: Inhibits DNA repair and replication by preventing the enzyme from resealing DNA after it has been cut.

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Clinical Uses

• Daunorubicin: Primarily used for acute leukemias (AML, ALL).

• Doxorubicin: Used in solid tumors (breast cancer, ovarian cancer, soft tissue sarcomas, etc.).

• Idarubicin: Primarily used for acute leukemias (similar to daunorubicin).

• Related Agent:

  • Mitoxantrone: An anthracycline-like agent, used for acute non-lymphocytic leukemia (ANLL).

• Newer Analogue:

  • Valrubicin: A newer anthracycline with similar mechanisms but designed for bladder cancer.

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Toxicities

• Cardiotoxicity:

  • Irreversible cardiomyopathy (due to free radical generation and lipid peroxidation in heart muscle).

  • Cumulative dose-dependent toxicity, leading to heart failure.

  • Cardiac monitoring is crucial during treatment.

• Mutagenic and Carcinogenic:

  • Can cause secondary cancers (leukemia) due to DNA damage.

• Other Side Effects:

  • Bone marrow suppression (leading to neutropenia, anemia, thrombocytopenia).

  • Gastrointestinal: Nausea, vomiting, and mucositis.

  • Extravasation: Can cause severe tissue damage if the drug leaks from the vein.

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Administration

• IV Administration: Anthracyclines are typically given via IV to minimize tissue damage and allow for controlled delivery to tumors.

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Summary Chart: Anthracyclines

Drug	Source	Main Use	Toxicities
Daunorubicin	Streptomyces peucetius	Acute leukemias (AML, ALL)	Cardiotoxicity, bone marrow suppression
Doxorubicin	Streptomyces peucetius	Solid tumors (e.g., breast, lung)	Cardiotoxicity, bone marrow suppression
Idarubicin	Synthetic	Acute leukemias (AML, ALL)	Cardiotoxicity, bone marrow suppression
Mitoxantrone	Synthetic, related	Acute non-lymphocytic leukemia	Cardiotoxicity, bone marrow suppression
Valrubicin	Synthetic	Bladder cancer	Similar to anthracycline toxicities

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Would you like more details on how to manage cardiotoxicity or the use of mitoxantrone for leukemia?

Bleomycins

DNA cleaving

Source Streptomyces verticillus

Squamous cell ca of head neck, cervix, lung, lymphoma, testicular tumours Minimal myelosuppressive and immunosupressive

Combination because of noo-orlapping toxicities

MOA oxidative damage to DNA

Pk

• IV or instillation in the bladder for bladder ca.

• Uses - germ cell tumours of testis and ovary

• Toxicity - hyperpigmentation, hyperkeratosis, erythema and keratosis

• Pulmonary fibrosis

Mitomycin

• Streptomyces caespitosus

• Cross link DNA and inhibit DNA synthesis

• IV

• Carcinoma colon and stomach

• Myelosuppression ,GIT symptoms, HUS

Other agents

• Enzymes - L-asparaginase deprive tumour cell of asparagine by hydrolysising it

• Used in leukaemias

• Hormones - adrenocorticosteroids, oestrogens ,progestins and androgens

• Inhibitors of hormones - aminoglutethimide

• Platinum compounds - cisplatin and carboplatin

• Hydoxyurea