MPP lecture 7

Questions and Answers

What is the primary goal of traditional antineoplastic therapies?

To increase the lifespan of normal rapidly dividing cells

To selectively target specific molecular pathways

To stop the rapid dividing of cancer cells (correct)

To enhance the immune response against cancer cells

Which of the following best describes the selectivity of traditional antineoplastic therapies?

Highly selective for cancer-specific proteins

Broad-spectrum, affecting both cancerous and normal cells (correct)

Only affects cancer cells with genetic markers

Targeted towards specific mutations in cancer cells

Which therapy is characterized by fewer and more manageable side effects?

Chemotherapy

Topoisomerase inhibitors

Alkylating agents

Signal target antineoplastic therapies (correct)

What type of agents are examples of traditional antineoplastic therapies?

Alkylating agents Signup and view all the answers

What is a common mechanism through which traditional antineoplastic therapies achieve their effect?

Interfering with cell division and damaging DNA Signup and view all the answers

Which of the following therapies targets specific cancer-related pathways?

Tyrosine kinase inhibitors Signup and view all the answers

What is a potential drawback of signal target antineoplastic therapies?

They may affect normal tissues sharing similar molecular pathways. Signup and view all the answers

Which of the following statements about the mitotoxicity hypothesis is true?

It suggests that rapidly dividing normal cells are susceptible to drugs. Signup and view all the answers

Which mechanism is primarily responsible for the resistance to imatinib that dasatinib addresses?

Overcoming BCR-ABL mutations Signup and view all the answers

What is the key distinguishing feature of nilotinib compared to imatinib?

Nilotinib binds to the ATP-binding site with higher affinity Signup and view all the answers

How do Ras inhibitors primarily affect cancer cell survival?

By blocking Ras activation and function Signup and view all the answers

What role does the mTOR pathway play in cellular processes?

It is a central regulator of cell growth and proliferation Signup and view all the answers

What is the role of sorafenib as a multi-kinase inhibitor?

It inhibits several RAF kinases Signup and view all the answers

Which of the following is true about farnesyltransferase inhibitors (FTIs)?

They prevent Ras from being anchored to the membrane Signup and view all the answers

Which of the following best describes the combined action of dasatinib and nilotinib?

Both inhibit BCR-ABL by binding to different conformations Signup and view all the answers

What cellular process does the inhibition of the mTOR pathway primarily affect?

Translation of growth signals into cellular responses Signup and view all the answers

Which statement is accurate regarding dasatinib and its mechanism of action?

It inhibits BCR-ABL by binding to both conformations Signup and view all the answers

What is the primary mechanism of action for rapamycin?

It inhibits mTORC1 by binding to FKBP12. Signup and view all the answers

How does temsirolimus primarily function in cancer treatment?

It inhibits mTORC1, impacting tumor growth and survival. Signup and view all the answers

What consequence arises from the inhibition of JAK2 activity?

Prevention of STAT activation and downstream signaling. Signup and view all the answers

What role do proteasome inhibitors like Bortezomib play in cancer therapy?

They prevent degradation of regulatory proteins, leading to apoptosis. Signup and view all the answers

What is the function of the JAK-STAT signaling pathway?

To facilitate the phosphorylation of STATs leading to transcription factor activity. Signup and view all the answers

What is a critical aspect of microtubule dynamics important for mitosis?

Rapid assembly and disassembly of microtubules is essential. Signup and view all the answers

Which effect results from blocking the function of microtubules with pharmacologic agents?

Prevention of mitosis and cell division. Signup and view all the answers

What is one consequence of protein accumulation due to proteasome inhibition?

Activation of pro-apoptotic factors. Signup and view all the answers

Why is it important to understand the mechanisms of drugs like rapamycin and temsirolimus?

They provide insight into cancer treatment and cellular signaling. Signup and view all the answers

What distinguishes Vinca Alkaloids from Taxanes in their mechanism of action on microtubules?

Vinca Alkaloids promote microtubule depolymerization while Taxanes inhibit it. Signup and view all the answers

Which of the following statements accurately describes the role of alkylating agents in cancer treatment?

They attach alkyl groups to DNA, causing structural alterations. Signup and view all the answers

What is a key characteristic of platinum complexes like Cisplatin in cancer therapy?

They emulate the action of alkylating agents by targeting DNA nucleophilic sites. Signup and view all the answers

Among the following agents, which type has a primary mechanism that involves damaging the integrity of DNA?

Topoisomerase inhibitors. Signup and view all the answers

Which of the following best describes the impact of an oncogenic mutation of ras in malignancy?

It is a common event influencing around 30% of cancers. Signup and view all the answers

What is the primary mechanism of action of gefitinib?

Block the ATP-binding site of the EGFR kinase Signup and view all the answers

Which of the following statements about cetuximab is true?

It binds to the extracellular domain of EGFR, preventing ligand binding. Signup and view all the answers

What type of drug is Erlotinib classified as?

Tyrosine kinase inhibitor Signup and view all the answers

Which type of cancer is primarily treated with Imatinib?

Chronic myeloid leukemia Signup and view all the answers

What characteristic is true of Trastuzumab's mechanism?

It reduces cancer recurrence by 50% by blocking ErbB2 signaling. Signup and view all the answers

What differentiates dasatinib from imatinib?

Dasatinib can inhibit both BCR-ABL and Src family kinases. Signup and view all the answers

Why do EGFR antagonists like gefitinib and erlotinib primarily benefit tumors with activating EGFR mutations?

These mutations increase the reliance on EGFR signaling, making inhibition more effective. Signup and view all the answers

Which of the following is a key feature of the action of BCR-ABL inhibitors?

They inhibit tyrosine kinase activity to prevent cell proliferation. Signup and view all the answers

What type of drug is cetuximab considered?

Monoclonal antibody Signup and view all the answers

Study Notes

Traditional Antineoplastic Therapies

Broad-spectrum activities target both cancerous and normal rapidly dividing cells, leading to significant side effects.
Aim to halt rapid division of cancer cells, with tumors being most vulnerable during growth phases.
Based on "Mitotoxicity Hypothesis", emphasizing susceptibility of metabolically active cells to growth-interfering drugs.
Mechanisms include interference with cell division (mitosis) and DNA damage to inhibit cancer proliferation.
Examples include alkylating agents, antimetabolites, topoisomerase inhibitors, and microtubule inhibitors.
Non-specific selectivity results in damage to healthy rapidly dividing cells, such as bone marrow, hair follicles, and gastrointestinal linings.
Adverse effects stem from high toxicity due to collateral damage to normal cells.

Signal Target Antineoplastic Therapies

More precise approaches target specific cancer-related molecular pathways, resulting in fewer side effects.
Mechanisms involve specific targets like proteins, receptors, or mutations crucial for cancer cell survival.
Examples include tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and immune checkpoint inhibitors.
High selectivity means reduced impact on normal cells, although some off-target effects may occur due to similarities in protein families.

EGFR Antagonists

Include gefitinib, erlotinib, cetuximab, and trastuzumab.
Gefitinib: Reversible TKI inhibiting EGFR kinase activity; blocks ATP-binding site, reducing cancer cell growth signals.
Erlotinib: TKI that inhibits EGFR's tyrosine kinase domain, blocking cell proliferation signals and improving survival outcomes.
Cetuximab: Monoclonal antibody targeting EGFR (ErbB1); prevents ligand binding, receptor activation, and engages the immune system.
Trastuzumab: Monoclonal antibody targeting EGFR (ErbB2); blocks signaling, significantly reducing cancer recurrence rates.

BCR-ABL Inhibitors

Include imatinib, dasatinib, and nilotinib.
Imatinib: TKI binding to ATP site of BCR-ABL fusion protein, inhibiting tyrosine kinase activity, thus blocking pathways promoting cell proliferation in CML and ALL.
Dasatinib: Dual SRC-ABL inhibitor; binds to active and inactive forms of BCR-ABL to alleviate imatinib resistance.
Nilotinib: TKI with higher binding affinity than imatinib; effective against resistant cases by more effectively inhibiting the BCR-ABL protein.

Ras/MAPK and mTOR Inhibitors

Ras Inhibitors: Target Ras protein involved in cell growth signaling; block activation, impairing downstream MAPK pathway.
FTIs: Inhibit RAS farnesylation, preventing its activation and disrupting signaling.
Sorafenib: Multi-kinase inhibitor affecting RAF kinases in the Ras signaling pathway; reduces proliferation and induces apoptosis.
mTOR Inhibitors: Block mTOR pathway, crucial for cell growth; regulates responses to growth signals.
Rapamycin and Temsirolimus: Both inhibit mTORC1, decreasing proliferation and promoting apoptosis.

JAK-STAT Pathway and Inhibitors

JAK-STAT Pathway: JAKs phosphorylate STATs, facilitating their role as transcription factors for gene regulation.
JAK2 Inhibitors: Block JAK2 activity, inhibiting STAT activation and reducing cell proliferation associated with JAK2 dysregulation.

Proteasome Inhibitors

Bortezomib: Inhibits proteasome function, preventing degradation of regulatory proteins; leads to increased apoptosis and disrupted signaling pathways in cancer cells.

Microtubule Dynamics in Mitosis

Microtubules rapidly assemble/disassemble for physiological functions.
Pharmacological agents disrupt microtubule function by preventing tubulin assembly or stabilizing existing microtubules.

Chemotherapeutic Agent Classes

DNA Damaging Agents:
- Alkylating agents modify DNA structure (e.g., cyclophosphamide, mechlorethamine).
- Platinum compounds (e.g., cisplatin) act similarly, crucial for certain cancers.
Inhibitors of DNA Synthesis: Antimetabolites and topoisomerase inhibitors.
Microtubule Function Inhibitors:
- Vinca alkaloids prevent microtubule polymerization.
- Taxanes promote polymerization while inhibiting depolymerization.

Mechanisms of Action for Selected Agents

Alkylating Agents: Attach alkyl groups to DNA to disrupt function.
Platinum Compounds: Bind DNA, potentially causing breaks.
Microtubule Inhibitors: Target tubulin functions to affect cell division and proliferation.

Clinical Implications

Oncogenic mutation of Ras is prevalent in 30% of cancers, indicating its critical role in malignancies.

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Explore the mechanisms of action and adverse effects of signal target antineoplastic therapies versus traditional ones. This quiz helps you understand the differences in how these therapies work and their impact on both cancerous and normal cells.