Increased expression of the mdr-1 gene encoding the drug efflux pump P-glycoprotein is a well-established mediator of acquired drug resistance in vitro, and a similar role has been hypothesized in vivo in human malignancy.
The mdr1P-glycoprotein is over-expressed in multidrug resistant (MDR) tumor cells and is believed to play a role in the elimination of certain cytotoxic drugs used in the chemotherapy of cancer.
Multidrug resistance for many types of cancer outside the central nervous system (CNS) has been found to be due to the overexpression of the multidrug resistance gene MDR1, of which the gene-product P-glycoprotein acts as a membrane-bound efflux pump for many anticancer drugs.
P-glycoprotein is also expressed in many normal human tissues, e.g., in the gastrointestinal tract, and this may be the reason for intrinsic resistance observed clinically in cancers derived from certain tissues.
Recently, Vasanthakumar and Ahmed reported (Vasanthakumar, G.; Ahmed, N.K., Cancer Communications 1:225-232; 1989) a complete inhibition of the multiple drug resistance gene (MDR1) in the K562/III erythroleukemia cells, using a 15 bases-long methylphosphonate oligodeoxynucleotide analog.
However, in contrast to cell lines exhibiting multidrug resistance (MDR) associated with overexpression of P-glycoprotein, this line is not cross-resistant to the Vinca alkaloids, is not impaired in drug accumulation, and does not overexpress the mdrl gene (Cancer Res., 47: 1297, 5455, 1987).
MDR1 RNA levels were occasionally elevated in other untreated cancers, including neuroblastoma, acute lymphocytic leukemia (ALL) in adults, acute nonlymphocytic leukemia (ANLL) in adults, and indolent non-Hodgkin's lymphoma.
We report here a combination of immunomagnetic purification of cancer cells and reverse transcriptase polymerase chain reaction (RT-PCR) that enables highly sensitive detection of multidrug resistance gene 1 (MDR1)-mRNA levels in human breast carcinoma cells obtained from fine needle aspirates (FNA).
The initial goal of such trials is to demonstrate the ability to reverse MDR1-mediated drug resistance in the appropriate advanced refractory malignancies.
Measurement of P-glycoprotein and the gene that encodes it, mdr-1, is an important tool for assessing the impact of multidrug resistance in clinical cancer.
Because several clinical trials have already been initiated to determine whether pharmacologic chemosensitization improves the outcome of chemotherapy in certain malignancies, the successful verification of multidrug resistance limiting the cure rates of these tumors becomes a more critical issue, and identification of those patients with lower levels of P-glycoprotein expression early in the course of their disease, when they are most likely to benefit from multidrug resistance reversal, has assumed an even greater relevance.
Extensive clinical studies have shown that P-glycoprotein is expressed on virtually all types of haematological malignancies, including acute and chronic leukaemias, multiple myelomas and malignant lymphomas.
The resistance of malignant tumors to chemotherapy with anticancer drugs has been considered to be due partly to overexpression of the multidrug resistance gene (mdr1) and its gene product, P-glycoprotein (P-GP), which acts as a drug efflux pump for several chemotherapeutic agents.
P-glycoprotein (P-gP) has been implicated as playing a role in multidrug (MDR) resistance in cancer, chloroquine-resistant Plasmodium falciparum infection, and possibly human immunodeficiency virus-1 (HIV-1) resistance to nucleoside compounds.
Furthermore, the ability to select for the presence of the MDR1 cDNA in vivo means that it can be used to introduce otherwise nonselectable genes into the bone marrow for therapy of cancer and other diseases.
Soluble P-glycoprotein also is detected in extracellular fluids of cancer patients, such as malignant ascites and serum, and is not detectable in serum samples of normal healthy individuals.
To study the future clinical implications of multidrug resistance, we have gathered data in the literature on the presence of P-gp in haematological malignancies.
This approach may be applicable to cancer patients as a specific means to reverse tumors with P-glycoprotein-mediated MDR phenotype back to a drug-sensitive one.
We have used this assay to measure mdr1 expression in a multiple myeloma cell line, 8226/S, its drug resistant variants 8226/dox6 and 8226/dox40, and tumor samples from 10 patients with B-cell malignancies (9 multiple myeloma, 1 chronic lymphocytic leukemia).8226/S does not express mdr1 mRNA.
Pharmacologically active in vivo doses of P-glycoprotein (Pgp) blockers, specifically verapamil, Cremophor EL and PSC833 cause toxicity in addition to that from the concomitantly used cancer chemotherapeutic drugs.