2 genetic changes of cancer
- - dominant gain of function ie, amplification, translocation and mutation
- - recessive loss of function, ie, Rb and p53
Besides genetic changes, what other defect in cells that lead to oncogenesis?
regulation circuits that govern normal cell proliferation and homeostasis
Goal of antineoplastic agent
eliminating and destroying neoplastic cells
Antineoplastic agent - general toxicities
nausea, vomiting, fatigue, anemia, immunosuppression, leucopenia, alopecia, oral mucositis
Interact with DNA causing substitution reactions, cross-linking reactions or strand breaks.
Forming alky radicals, which form covalent linkages with nucleophilic moieties such as the phosphate, sulfhydryl, hydroxyl, carboxyl, amino, and imidazole groups.
Alkylating agent - dacarbazine
purine precursor for treatment of metastatic melanoma, Hodgkin’s disease
alkylating agent - cisplatin
it reacts directly with sulfur groups (such as glutathion), cross-links in DNA
Cytotoxic effects via similarity in structure or function to naturally occurring metabolites involved in nucleic acid synthesis -either inhibit enzymes involved in nucleic acid synthesis or produce incorrect codes
antibetabolite - methotrexate
dihydrofolate raductase inhibitor
antimetabobites - purine & pyrimidine analogues
specific for S phase by interfering with DNA synthesis
cytotoxic properties - by binding with DNA to produce irreversible complexes that inhibit cell division
antitumor antibiotics - actinomycin D
The drug intercalates into DNA between adjacent guanine-cytosine base pairs and inhibits DNA-directed RNA synthesis.
Antitumor Antibiotics - andriamycin
The drug combines with DNA in an intercalative mode by slipping into the helical structure between stacked base. Therefore, biosynthesis of macromolecular and replication are inhibited.
- * Also inhibits the progression of the
- enzyme topoisomerase to unwind DNA for transcription.
- * For treatment of wide spectrum of solid
Antitumor antibiotics - bleomycin
The cytotoxic action of bleomycin has been attributed to DNA scission and fragmentation with inhibition of the usual DNA repair mechanisms.
Bleomycin is cell phase specific: major effects on G2 and M phases of the cell cycle. For treatment of Hodgkin’s and non-Hodgkin’s lymphomas, squamous cell carcinoma.
Antitumor antibiotics - mitomycin
- it reacts with DNA in the manner of the alkylating agents. Binding to DNA leads to
- cross-linking and inhibition of RNA synthesis.
In combination with other antitumor drugs for the treatment a number of solid tumors
- MofA: The vinca alkaloids has been attributed to their capacity to arrest cell division in metaphase by binding to the microtubular protein (tubulin) that forms the
- mitotic spindle.
For treatment of several types of cancer including leukemia, lymphoma, melanoma and breast cancers
- Disrupt equilibrium between free
- tubulin and microtubules causing stabilization of cytoplasmic microtubules and thereby inhibits depolymerization. Subsequently, disrupts the normal dynamic reorganization of the microtuble network required for mitosis.
For the treatment of breast & ovarian cancers
Use agent with different cell cycle specificity, mechanisms of actions, toxicities, and potential combination for synergy.
Administer the drugs intermittent courses and at maximal tolerated doses to maximize cell kill, allow for host recovery, and avoid prolonged drug-free intervals.
tx for advanced Hodgkin's disease
Alternating non-cross-resistant regimen: ABVD and MOPP
alternating the 2 regiment monthly or combine the 2 regimen into a monthly cycle
Combination regimens containing cisplatin and fluorouracil require ... simultaneously
The ultimate dose-intensive regimens include high dose chemotherapy, with or without irradiation, requiring ...
bone marrow transplantation or peripheral stem cell reinfusion to rescue the host from total marrow aplasia
Risk Factors for oral Cancer
HPV infection (relate to p53, RB and E7)
chewing quids of betel
Alcohol Radiation exposure
Long-term irritation caused by ill-fitting dentures (inflammation lead to oncogenesis)
Treatment for oral cancer
- Cisplatin, 5- Fluorouracil, carboplatin, paclitaxel
Tumor growth factors: tageting EGFR
EGFR blocking agents
EGFR antibodies and tyrosine kinase inhibitors
Direct toxicities of cancer therapy - oral complication
- Oral mucositis
- salivary gland dysfunction
- neurotoxicity: taste dysfunction, dentinal hypersensitivity
- temporomandibular dysfunction
- dental and skeletal growth and
- developmental anomalies (pediatric patient)