Diseases Disorders
Chemotherapy agents work by interrupting the cell cycle. This occurs at the many different stages of cell cycling and replication of the cell. The known stages of the cell cycle include the G1, S (DNA synthesis stage), G2, and M phase (mitosis). There is also a resting phase, termed G0 which is the phase in which cells are reesistent to chemotherapy agents, as the cell is not replicating or changing, and therefore, no chemotherapeutic agents can be incorporated into the cell.
These include nitrogen mustard, cyclophasphamide, ifosfamide, chlorambucil, melphalan, busulfan. There mechanism of actioon is through alkylation. The reactive alkyl groups found on these molecules form bonds with DNA in the cancer cells. This DNA becomes cross-linked through the bond formations, and there is breakage of the DNA strands. The cell subsequenlty dies. These agents are cell cycle non-specific.
Alkylating agents have a myelosuppression effect on the bone marrow, thereby decreasing blood cells, including red blood cells, and white blood cells. These patients are prone to anemia, bleeding and infections. Nausea nad vomitting is also common in these drugs, as the gut cells are unable to renew and maintain a barrier function in the gastrointestinal tract. Mucositis is common with cyclophosphamide use, as well as alopeica (also with ifosfamide). Both these drugs can also cause hemorrhagic cystitis. Busulfan can cause pulmonary toxicity also.
Alkylating agents are numerous long-term effects that are worrisome. There is a chance of infertility depending on the length of chemotherapy treatment with alkylating agents. Pulmonary damage is common, as well as secondary malignancies due to the effect of these agents on the bone marrow.
The incidenceof ifosfamide related neurotoxicity is around 10-25%. It presents most commonly with confusion, mutism, hallucinations, agitation, and can lead to coma. The treatment is with methylene blue 50 mg IV. Prophylaxis is also with methylene blue. Hypnotics, as well as any types of sedatives, should be avoided with ifosfamide treatments, as there may be drug interactions at the level of drug clearance by the liver.
Hemorrhagic cystitis is caused by alkylating agents, secondary to oxazaphosphorines, such as ifosfamide and cyclophosphamide. This is now prevented with the use of mesna, which reacts with acrolein to form stable, non-urotoxic compounds which can easily be excreted. Dosing is usually as an IV bolus.
Antimetabolite chemotherapeutic agents act simply by competing with the normal metabolites of cells, thereby depleting the agents needed by enzymes to make larger molecules to are needed to make a new cell during replication. Moreover, these agents can alternatively substitute for a metabolite that is normally incorporated into DNA or RNA molecules, thereby forming defective molecules.
Antimetabolite agents include folate antagonists (folate is the main component of DNA subunits), such as methotrexate and pemetrexed, purine antagonists, such aas 6-mercaptopurine, dacarbazine, fludarabine, thioquanine, pyrimidine antagonists, such as 5-fluorouracil, cytarabine, gemcitabine, capecitabine. All these agents work when the cell requires molecules in order to replicate its DNA or duplicate the cell in size so it can split into two. Therefore, these agents are cell-cycle specific as they are active during the DNA synthesis stage of the cell-cycle, the S phase.
Antimetabolite Agents have numerous side-effects. These include myelosuppression, similarly as with the alkylating agents mentioned previously, nausea and vomitting, mucositis is very common, and alopecia can be found with methotrexate, cytarabine and 5-fluorouracil. In addition, methotrexate is known to cause liver and kidney damage. Kidney damage occurs as methotrexate easily precipitates within the renal tubules, and is toxic in this form. Gemcitabine is also commonly associated with a maculopapular rash that responds well to topical steroids, and anti-histamines.
Methotrexate is a antimetabolite chemotherapy agent that binds and depletes a cells stores of folate. It completely inhibits dihydrofolate reductase, thereby blocking tetrahydrofolate synthesis, which is required for nucleotide (DNA pieces) precursors. This inhibits nucleic acid synthesis, such as DNA, RNA, and subsequently protein synthesis through RNA blockage. Therefore, this agent works very quickly. This inhibition can be relieved through the use of folinic acid, not folic acid !! Addition of folinic acid allows cells to resume DNA synthesis. It is believed that highly aggressive, cancer, cells would have picked up methotrexatete before the normal cells, thereby being affected the most by the agent. The normal cells, which are less aggressively growing, are less effected by the methotrexate, and can be rescued by the folinic acid. This is a timed rescue with folinic acid, which occures in 24-36 hours. Folinic acid is a tetrrahydrofolate acid derivative. In general, the methotrexate saturates the cancer cell receptors at high concentrations, and therefore not much folinic acid can be taken up by the cancer cells.
Prevention of methotrexate kidney damage, which is caused by methotrexate precipitating within the renal tubules, is done through alkalinization of the urine. This change in pH of urine occurs through the use of PO or IV sodium bicarbonate with forced diuresis. The forced diuresis prevents the methotrexate from precipitating within the renal tubules. Dipstick and foleys can also help. Risk factors that can make kidney damage more likely and more difficult to treat, is the presence of any extra body fluids or rerserviors, such as with ascites, pleural effusions, dehydration, which allow methotrexate to either be at a higher than expected concentration, or act by keeping methotrexate within a pool that slowly releases the drug into the circulation over a very long time.
5-Florouracil active inhibits thymidylate synthetase and the production of thymidine by forming a stable irreversible complex. Folinic acid can be used in this state, to increase the effect of 5-florouracil activity. Folinic acid must, however, be given prior to 5-fluorouracil.
1) Robbins and Cotran Pathologic Basis of Disease. Seventh Edition. Kumar, V., Abbas, A.K., and Fausto, N. 2005, Elsevier Inc.