Reduced drug accumulation as the mechanism of extreme clinical resistance to methotrexate in the human T-cell leukemia xenograft, LALW-2

Article Abstract:

In many cases, cancers that develop after a period of remission are more resistant to chemotherapy than the original tumor. The phenomenon of drug resistance obviously has an important influence on the successful treatment of recurrent cancer. Many of the studies of drug resistance have been conducted with laboratory cultures of tumor cells, and it is not certain that the mechanisms of resistance observed under these conditions are identical to those at work in the cancer patient. Methotrexate is a chemotherapeutic agent that works by inhibiting the enzyme dihydrofolate reductase (DHFR). There appear to be several mechanisms by which cancer cells may become resistant to this drug. One is by gene amplification; additional copies of the DHFR gene are made, and the resulting increase in the number of enzyme molecules makes the cell more resistant to the drug. A mutation in the DHFR gene may also alter the structure of the molecule in a way that makes methotrexate a less efficient inhibitor. A third mechanism for resistance is a change in the uptake mechanism; less methotrexate is brought into the cell, and therefore a dose of methotrexate has less effect. In laboratory culture conditions, resistance to smaller concentrations of methotrexate appear to result from reduction in the transport of the drug into the cell. Resistance to higher concentrations results from DHFR gene amplification; this mechanism has received the greatest research attention. A study was conducted to determine the mechanism of drug resistance in a line of leukemic T cells growing in the laboratory. In contrast with many other studies, the resistance of these cell cultures developed in the patient's body, not as the result of drug exposure in laboratory flasks. Although this cell line is resistant to very high concentrations of methotrexate (one millimolar or 454 milligrams per liter), no evidence could be found for amplification of the DHFR gene. Similarly, there was no evidence that the binding of the drug to the enzyme was altered in these cells. However, the accumulation of methotrexate in the cells was reduced, indicating that within the patient's body, the cells became resistance to methotrexate as a result of a reduction of the transport of the into the cell. (Consumer Summary produced by Reliance Medical Information, Inc.)

Physiological aspects, Leukemia, Chemotherapy, Drug resistance, Methotrexate

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Malignant angioendotheliomatosis presenting as disseminated intravascular coagulopathy

Article Abstract:

Many coagulation disorders involve only specific structures in the body. Disseminated intravascular coagulation is diffuse and can result in blood coagulation all through the body. Ironically, the coagulation may use up so much of the blood's coagulating capacity that hemorrhage may occur as a complication. Disseminated intravascular coagulation (DIC) is not a disease in its own right, but rather a condition that can result from the effects of a variety of different diseases. In most cases of DIC, the patient has already been diagnosed with some disorder predisposing him to DIC, and there is little need to evaluate the cause of the DIC further. However, on occasion DIC may develop in an individual with no apparent cause. The authors recount an unusual case in which a rare form of lymphoma led to DIC and related symptoms. The patient exhibited fever, anasarca (severe edema in most body tissues), and hemolytic anemia. The patient had an enlarged spleen, and when the spleen was removed the patient experienced some improvement. However, her symptoms returned. Laboratory tests revealed abnormalities, some of which indicated a coagulation abnormality. Further coagulation studies suggested DIC. The suggestion of DIC and the patient's edema suggested that small blood vessels might have been involved in the patient's disease symptoms. A biopsy was performed on both skin and muscle; examination of the specimens revealed a large-cell lymphoma invading capillaries and small veins and arteries. This rare lymphoma is malignant angioendotheliomatosis, which has been previously thought to arise from blood vessel cells themselves. This case illustrates that indications of DIC with no obvious cause should raise suspicion of a hidden pathological process affecting the blood vessels. In the present case, the angioendotheliomatosis was treated with chemotherapy, but the patient was unable to stay remission and died with a relapse in the central nervous system 19 months after the initial diagnosis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Case studies, Diagnosis, Causes of, Blood clotting disorders, Blood coagulation disorders, Lymphomas, Disseminated intravascular coagulation

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