Rodent Leukemia Model

Resembles first order kinetics

A constant fraction is being eliminated

ex.  If you start with 100 tumor cells and 50% is eliminated every time then with one half life you have 50 tumor cells, with two half lives you have 25 cells. 

Most solid tumors do not follow this model.

Most solid tumors display Gompertzian kinetics

As the tumor grows larger less cells are actively proliferating.

Each dose does not kill a constant fraction of cells.

Major Problem in Chemotherapy

May occur de novo

Gene amplification

P-glycoprotein-mediates efflux of multiple drugs

Goal is to produce maximum efficacy with tolerable toxicity

1. Each drug individually active against tumor

2. Mechanisms of interaction produce optimum effect (synergistic)

3. Drugs that have different major toxic effects

4. Other:optimum drug dosage, optimum drug scheduling

Alkylating Agents

Drugs: Mechlorethamine

Melphalan

Cyclophosphamide

Chlorambucil

Involves the formation of cyclic imonium or carbonium ion intermediate that Rxs with tissue nucleophiles --> alkylation of molecules.

Interferes with nucleic acid synthesis and function.

With bifunctional agents 2nd group can be activated and alkylated 2nd nucleophile.

Resistance involves DNA repair of DNA

Toxicites: Myelosupression, GI (nausea, vomiting), reproductive, carcinogenesis also possible.