Antineoplastics 1 Flashcards
Fraction of tumor cells in replicative phase
Growth fraction
Doubling time of proliferating cancer cells is constant, straight line on a semilog plot, cell kill 1st order kinetics
Skipper’s law
Cells accumulate slowly at first then there is rapid growth, growth rate about 1/3 of max tumor volume, sigmoid curve
Gompertzian growth
Active in al phases except g0
Phase nonspecific
Active in one phase of the cycle
Phase specific
Active even in g0
Cell cycle nonspecific
Cell cycle specific agents
Antimetabolites
Bleomycin
Podophyllin alkaloids (etoposide, vp-16, teniposide, vm 26)
Plant alkaloids (vincristine, vinblastine, paclitaxel)
Cell cycle nonspecific
Alkylating agents (busulfan, cyclophosphamide, mechlorethamine, melphalan, thiorepa)
Antibiotics (dactinomycin, daunorubicin, doxorubicin, plicamycin, mitomycin)
Cisplatin
Nitrosureas
Goals of cancer treatment
Cure
Palliative
Adjuvant
If 1g of tumor, 10^9 cells is the min size of early detection and 10^-5 is the tumor mutation rate per gene then such a tumor might contain 10^4 clones which might be resistant to a given drug
Goldie Coldman Hypothesis
Drug resistance mechanisms
Decreased drug transport into cell Reduced drug activation Increased drug or active metabolite inactivation Increased DNA repair Use of alternate pathway as source of metabolite Increased drug transport outside of cell Gene amplification of drug target Alteration of target to reduce binding
Advantages of combination chemotherapy
Higher response rate due to additive effects
Non overlapping host toxicities
Effective against broader range cell lines
May slow down development of or prevent resistance
Inhibits dihydrofolate reductase, inhibits purine and dtmp biosysnthesis
Methotrexate
Terminates dna chain elongation, incorporated into dna and rna
Cytarabine
Intercalates with dna disrupting its function
Dactinomycin
Daunorubicin
Doxorubicin
Inhibits de novo synthesis of purine ring
6 mercaptopurine thioguanine
Inhibits dTMP synthesis
5 fluorouracil
Scission of DNA by an oxidative process
Bleomycin peptide antibiotics
Crosslinks and fragments nucleic acids
Alkylating agents
Nitrosureas
Cisplatin
Alkylating agents moa
Alkylation of DNA at N7 of guanine
Cell cycle specific, alkylating agents?
NO! Nonspecific, but replicating cells are most susceptible
First of nitrogen mustard used clinically
Mechlorethamine
Fastest acting nitrogen mustard
Mechlorethamine
Hodgkin’s disease MOPP
Mustargen/mechlorethamine
Oncovin/vincristine
Procarbazine
Prednisone
ABVD, newer for hodgkins
Adriamycin (doxorubicin/hydroxydoxorubicin)
Bleomycin
Vinblastine
Dacarbazine (like procarbazine)
Mechlorethamine toxicities
Nausea and vomiting
Severe myelosuppression
Inc incidence of leukemias
Alkylating agent that is not a vesicant, needs to be converted to active form
Cyclophosphamide
Very broad spectrum, component of combination therapy
Cyclophosphamide
Less thrombocytopenia, more alopecia, less CNS effect compared to mechlorethamine
Cyclophosphamide
Phenylalanine derivative of nitrogen mustard, not a vesicant, oral
Melphalan
Bone marrow depression but
Infrequent nausea and vomiting
No alopecia
No renal, hepatic deficits
Melphalan
Slowest acting nitrogen mustard, bone marrow depression with high doses, long perio
Chlorambucil
Nitrosurea, similar to bifunctional alkylating agents but with carbamoylating activity, high lipophilicity, crosses BBB
BCNU (carmustine)
Alkylsulfonate
Busulfan
Pulmonary infiltrates and fibrosis
Busulfan
Inorganic water soluble platinum containing complex
Cisplatin
Nausea and vomiting
Nephrotoxicity delayed, dose limiting
OTOTOXICITY
Mild to mod myelosuppression
Cisplatin
Alkylating agents
Mechlorethamine Cyclophosphamide Busulfan Melphalan Chlorambucil BCNU (carmustine) Cisplatin
Nitrogen mustard
Mechlorethamine
Melphalan
Chlorambucil
