Antineoplastic 1 Flashcards
When cancer cannot be cured what are the goals of treatment?
- Shifts to palliation
- Amelioration of symptoms
- Preservation of quality of life
Types of Systemic Cancer Treatments?
- Conventional “cytotoxic” chemotherapy agents
- Targeted agents: Biologics (antibodies or cytokines)
- Hormonal therapies
- Biologic therapies: manipulate the host-tumor interaction in favor of the host.
Define Gompertzian tumor growth:
The growth fraction of a tumor declines exponentially over time.
Total Kill Hypothesis:
- Single cancer cell can multiply and kill the host
- For microbial infections a “3-log kill” by antibiotics may be sufficient to allow host defense mechanisms to eradicate the infection.
- For successful cancer treatment: All of the cancer cells must be killed.
Log-Kill Model by Skipper states what for a given dose of a drug?
It kills a constant fraction of cells, not a constant number, regardless of the cell numbers present.
Describe adjuvant chemotherapy?
Assumes the presence of undetectable cell masses after the initial surgical therapy that are capable of producing tumor relapse.
Clinically sequential use of drugs that works per Gompertzian growth.
- Cell-cycle nonspecific agents (cyclophosphamide) to bring down the mass.
- When tumor shrinks, proliferation begins.
- Cell-cycle specific agent (methotrexate)
- Kills the cell as it tries to proliferate.
Vinca Alkaloids work by what mechanism?
- Inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the mitotic spindle.
- Causes mitotic arrest at Metaphase, cell division stops, cell dies.
- Bind to B-tubulin and prevents interaction with a-tubulin.
What is the principal mechanism of resistance to Vinca Alkaloids?
Increased P-Glycoprotein
What are the three vinca alkaloids mentioned and what is said of them?
- Vincristine
- Neurotoxic
- Prednisone is useful in childhood leukemias.
- Vinblastine:
- Myelosuppressive (bone marrow suppression)
- Metastatic testicular cancer and Hodgkin’s lymphoma.
- Vinorelbine
Describe the mechanism and outcome of Taxanes?
- Hyper-stabilizes microtubule structure (freezes them)
- Taxanes bind to the B-subunit of tubulin, the resulting microtubule/taxane complex does not have the ability to disassemble.
- This adversely affects cell function and leads to apoptosis.
What Taxane is especially known for stocking and glove neuropathy?
Paclitaxel
What cancers have Taxanes become central treatments of?
Metastatic ovarian, breast, lung, GI, genitourinary, head and neck cancers.
What is the prototype of Epothilones and what is it approved for?
Ixabepilone
Metastatic Breast Cancer
What is the mechanism for Epothilones?
- They bind to B-tubulin and trigger microtubule nucleation at multiple sites away from centriole.
- Chaotic stabilization triggers cell cycle arrest at G2-M interface and apoptosis.
What step in the cell cycle do Topoisomerase inhibitors target?
S-phase Specfic
When are Topoisomerase I inhibitors used?
Ovarian and small cell lung carcinoma.
What is the mechanism for Topoisomerase I inhibitors?
- Initial cleavage action of topoisomerase I is not affected, but re-ligation step is.
- Leading to an accumulation of single-stranded breaks in DNA.
- Collision of a DNA replication fork with this cleaved strand causes an irreversible double-strand DNA break, leading to cell death.
What is the mechanism of Anthracyclines?
- Inhibition of Topoisomerase II
- Binding to DNA through intercalation
- Blocks synthesis of DNA and RNA, and DNA strand scission
- Generation of oxygen free radicals through an iron-dependent process.
What are the three Anthracyclines described in the lecture?
Doxorubicin
Daunorubicin
Mitoxantrone
Doxorubicin details
- Important anticancer drug
- Cons:
- Produces severe alopecia
- Potent vesicant (irritant)
- Toxicity: Cardiotoxic
- Acute: Arrhythmias
- Chronic: Digitalis-resistant congestive heart failure.
Role and Mechanism of Dexrazoxane
- Protects against doxorubicin-induced congestive heart failure.
- Prodrug that is hydrolyzed in heart cells to a metal chelating metabolite.
- Its likely function in preventing doxorubicin-induced damage to heart cells involves binding of ferric ions (Fe3+) by its chelating action.
Describe the Mechanism of Dactinomycin (Actinomycin-D)
- First Antibiotic shown to have anti-cancer activity
- Binds to ds-DNA through intercalation between adjacent guanine-cytosine base pairs.
- Inhibits transcription by binding to initiation complex and prevents elongation by RNA polymerase.
When is Dactinomycin used in cancer treatment?
- Treatment of rhabdomyosarcoma and Wilms tumor in children.
- In combo with primary surgery, radiotherapy, and other drugs.
Epipodophyllotoxins: Etoposide
inhibits?
Used for?
- Topoisomerase II
- Testicular tumors, when used with bleomycin and cisplatin.
- Small cell carcinoma of the lung when used with cisplatin and ifosfamide.
Downside of Epipodophyllotoxins: Etoposide
- Leukemogenic and may cause acute nonlymphocytic leukemia in children.
- Myelosuppression is the most common toxicity.
Downsides with Bleomycin?
- Toxicity to skin and lungs
- Pulmonary toxicity
- Pulmonary fibrosis (irreversible)
- Pulmonary toxicity
Mechanism of action for Bleomycin?
- Cleaves DNA
- Causes oxidative damage to deoxyribose of thymidylate and other nucleotides, leading to single- and ds breaks in DNA. Damaged cells accumulate in G2 phase.
Forms of cancer that Bleomycin is good against?
Germ cell testicular cancer
Hodgkin’s lymphoma
90% of patients with CML have what?
- Philadelphia Chromosome t(9:22)
- Encodes BCR-ABL non-receptor tyrosine kinase (w/ increased enzyme activity)
What are the results of BCR-ABL-dependent signaling?
- Enhanced Survival
- Inhibition of apoptosis
- Perturbation of cell adhesion and migration.
>90% of patients with CML were cured with?
Gleevec (imatinib)
Protein tyrosine kinase inhibitors have efficacy in diseases with what factors?
Common cancers?
- ABL, kit, PDGFR are dominant roles in driving the proliferation of the tumor.
- CML, gastrointestinal stromal tumors (GIST), chronic myelomonocytic leukemia.
Principle toxicity of BCR-ABL kinase inhibitors?
GI distress and fluid retention.
The IGF-1 receptor corresponds to what pathway?
PI3K
Used for Metastatic testicular cancer and Hodgkin’s Lymphoma
Is Neurotoxic
Vincristine
When used with prednisone is very useful for childhood leukemias
Also, Myelosuppressive
Vincristine
