Monitoring of Suspected Adverse Drug Reactions in Oncology Unit ...

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701
amplification of DHFR gene and thus an increase in the target enzyme, mutations in the DHFR gene, and
decreased ability to form methotrexate polyglutamate inside cells.
Methotrexate can be administered by several different routes including chronic oral, intermittent oral or
high-dose intravenous and intrathecal. Its absorption from the gastrointestinal tract depends on the dose,
with large doses being only partially absorbed while low doses are efficiently absorbed. These differences
are most likely due to dependence on a saturable folate carrier. At high doses methotrexate is most likely
taken up by passive diffusion. Only a small percentage crosses into the cerebrospinal fluid (CSF), thus
necessitating intrathecal administration for the treatment of tumor cells in the CNS. Approximately 50% of
the methotrexate is bound to plasma proteins thus there is the distinct possibility of drug interactions with
drugs that are also significantly bound to plasma proteins. Metabolism is usually minimal although after
administration in high dose 7-hydroxymethotrexate is formed which is potentially nephrotoxic. Elimination
is primarily renal and there is a clear relationship between serum levels of the drug and toxicity.
Methotrexate is useful for the treatment of several different tumors. It is the drug of choice for
gestational choriocarcinoma and related trophoblastic tumors of women where cures are obtained in a
substantial number of cases. In this cancer, it is usually used in combination with dactinomycin. In the
treatment of ALL in children, it is used for the maintenance of remissions. It is however of limited value for
adult leukemias. It has also been used for the treatment and prevention of leukemic meningitis where it is
given by intrathecal administration. Finally, high dose methotrexate along with leucovorin rescue is used
for the treatment of osteogenic sarcoma and leukemias and lymphomas.
The primary toxic effects are against the rapidly dividing cells of the bone marrow and gastrointestinal
epithelium. The severity of the clinical effects depends largely on the duration of exposure to inhibitory
levels of the drug. All of the stem-cell types of the marrow can be affected to produce leukopenia,
thrombocytopenia and with long-term administration, anemia. Methotrexate therapy must therefore be
modified according to the patient’s hematological status and leukocyte and platelet counts must be
carefully monitored. Mucositis is one of the earliest signs of toxicity and its appearance indicates that the
dose must be reduced or other serious toxicities will occur. If diarrhea and ulcerative stomatitis occur,
therapy with the drug must be stopped. Methotrexate causes kidney damage which is a frequent
complication of high dose therapy. Crystalline deposits of methotrexate and methotrexate derived materials
have been found in the renal tubules which seems to account for most of the nephrotoxicity. Alkalinizing
the urine to increase the solubility and ensuring good urine flow minimizes most of the nephrotoxicity due
to high-dose methotrexate. Both low and high dose therapy can cause hepatotoxicity. High dose therapy
results in elevated liver enzymes and low dose therapy produces a different type of hepatotoxicity which
includes cirrhosis. Methotrexate can cause a reversible pulmonary syndrome which has been observed
primarily in children undergoing maintenance therapy. Intrathecal and high-dose administration is
accompanied by several types of neurotoxicity. These range from acute manifestations to long-term
delayed toxicity in the form of encephalopathy. Nausea and anorexia frequently occur as acute side effects
of methotrexate therapy.
High dose methotrexate-rescue therapy: This involves administration of methotrexate at high doses along
with leucovorin to rescue host tissues from the effects of the intense methotrexate therapy. The leucovorin
provides the normal tissues with the reduced folate leucovorin which circumvents the inhibition of DHFR.
The protection seems to be selective in that it does not alter the antitumor effect of methotrexate.
Apparently, only the host cells are able to utilize the leucovorin. A more recent explanation is that of
differential reactivation of DHFR in host and tumor cells. Beneficial effects have been observed in patients
with osteosarcoma as well acute leukemia.
The two major anticancer drugs in the purine antimetabolite category are 6-mercaptopurine (6-MP)
and 6-thioguanine (6-TG). These drugs are analogs of hypoxanthine and guanine, respectively. Several
other purine analogs are also now commercially available. Among these compounds are not only anticancer
drugs but immunosuppressive agents (e.g. azathioprine) and antiviral compounds (e.g. aciclovir,
ganciclovir). The antipurines can both inhibit nucleotide and nucleic acid synthesis and be incorporated into
nucleic acid. Sometimes they can do both.
Thiopurines work at multiple sites. They must first be converted into the nucleotide form in order to be
active. This conversion is catalyzed by phosphoribosyltransferase enzymes. The nucleotide forms inhibit
the first committed step in the de novo purine synthesis pathway, that catalyzed by phosphoribosyl
pyrophosphate amidotransferase, and the key step in guanine nucleotide biosynthesis, catalyzed by inositol
Vol. 1 (2) Oct – Dec 2010 www.ijrpbsonline.com 10