Page 998 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 881

Acute Myeloid Leukemia patients older than the age of 60 years. No benefit in response rate
or survival was noted. Likewise, in a CALGB study, in adults with
An earlier meta-analysis of studies that examined the expression of untreated leukemia younger than the age of 60 years, PSC833 also
MDR1/PGP in blasts of patients with AML found that 40% (105 did not improve survival or response rates. Thus, the future role of
out of 261 patients) who were PGP positive achieved a CR, but 81% modulation of PGP in leukemia management remains ill defined.
(192 out of 238) of PGP-negative patients obtained a CR. An analysis
of 96 untreated patients with AML showed that PGP expression Multidrug Resistance-Associated Protein (ABC G2
predicted induction failure (p < .0001) and decreased OS (p < .001),
as did unfavorable cytogenetics. PGP expression was not detected in Transporter)
patients with favorable cytogenetic abnormalities [t(15;17), inv(16),
t(8;21)], was found in 29% of those samples with a normal karyotype, Structure and Function
and was expressed in 62% of patients with an unfavorable cytogenetic
abnormality. PGP was also detected in 63% of those with secondary The MRP was first described in 1992 in the doxorubicin-selected
AML compared with 25% of those with de novo disease. PGP analysis small-cell lung cancer cell line, and its biochemical characteristics and
18
with the MRK16 antibody in 211 elderly patients (older than 55 biologic properties have been reviewed. It has now been classified
years) with untreated AML again showed that PGP expression is within the larger context of ABC transporters, termed ABC G2
significantly associated with a decreased CR rate and resistant disease. transporters. Because much of the literature uses the MRP nomencla-
Patients in this report with de novo PGP-negative AML with favor- ture, we refer to this herein except for the studies using the ABC
able cytogenetics have a CR rate of 81% compared with 12% for terminology. This N-glycosylated plasma membrane phosphoprotein
those with secondary AML, which is PGP positive and has unfavor- has a molecular mass of 190 kDa (1531 amino acids) and is a member
able cytogenetics. Clinical trials using the PGP substrate Valspodar of the ABC transporter superfamily (see Table 57.7 and Fig. 57.11).
(PSC833) acting as a competitive inhibitor did not show the dramatic This transporter has 18 transmembrane domains (12 in the amino
benefit expected, especially in older patients with acute leukemias. end and six in the carboxyl end) and is coded on human chromosome
16p13.1.
The overexpression of MRP has been shown in vitro to result in
Impact of P-Glycoprotein in Other Hematologic different levels of drug resistance to several classes of antineoplastic
Malignancies agents, represented by actinomycin D, chlorambucil, melphalan,
cisplatin (CDDP), daunomycin, doxorubicin, epirubicin, teniposide
The role of PGP in the drug resistance of NHL, myeloma, and ALL (VM-26), etoposide (VP-16), and vincristine. Low levels of resistance
is ill defined. CLL is another chronic leukemia in which few PGP- have also been reported for taxol, vinblastine, and colchicine. In
related antineoplastic agents are used. However, a single study has addition to antitumoral agents, MRPs (and its isoforms) are capable
shown a correlation between MDR1 expression and survival, in which of transporting heavy metals (arsenicals, cadmium, and antimonials)
the 10 B-CLL patients who were MDR1 positive had a median as well as glutathione conjugates and cysteinyl leukotriene. Com-
survival of 19 months compared with 46 months for the 17 patients pounds reported to modulate MRP-mediated drug resistance in vitro
who were MDR1 negative (p < .01). Nonetheless, a recent study include the calcium channel blocker verapamil nocardipine; the
identified bortezomib as a substrate for PGP, raising the possibility
that myeloma PGP levels affect clinical response. There have not been
recent studies of the role of PGP in drug resistance in NHL in the
past 5 years. With the newer kinase inhibitors, it has recently been
noted that nilotinib and dasatinib are high-affinity substrates of Plasma
ABCG2. These agents appear to inhibit the function of this trans- membrane
porter, but whether this will translate into clinical impact has not COOH
received prospective attention.
NH
2
Clinical Studies With Modulators of P-Glycoprotein A NBD1 Linker NBD2
region
The clinical trials that have used various modulators of PGP have been
reviewed by several investigators. An early study in VAD-refractory Plasma
MM resulted in short-lived PRs to VAD plus racemic verapamil in membrane
five out of 22 patients. Four of the five responders overexpressed PGP; COOH
however, cardiac side effects precluded further dose escalation of IV NH
R,S-verapamil. Continuous IV infusion of CSA with VAD in VAD- 2
resistant myeloma patients resulted in seven out of 15 responses, which
were more common in those who overexpressed PGP. A randomized B NBD1 Linker NBD2
SWOG phase III study of VAD and PO verapamil in 120 patients region
with refractory myeloma demonstrated a 41% and 36% response in Fig. 57.11 MODELS OF MULTIDRUG-RESISTANCE PROTEIN
the VAD and VAD/verapamil arms, respectively, with median survival MEMBRANE TOPOLOGY. Multidrug-resistance protein (MRP) possesses
times of 10 and 13 months, respectively. Continuous-infusion CSA features common to all members of the ATP-binding cassette transporter
has been dose escalated in combination with daunorubicin and ara-C. superfamily in that each half of the protein is predicted to consist of several
Transient hyperbilirubinemia was seen in 62% of the patients; these transmembrane domains followed by a cytosolic nucleotide-binding domain
same patients had increased serum daunorubicin levels and a higher (MBD). The first model (A) is based on computer-assisted hydropathy analy-
response rate. A CR was seen in 26 out of 42 patients; however, the ses of the human MRP amino acid sequence and predicts that MRP is
MDR phenotype was not found to influence the response. A study composed of 12 transmembrane domains (solid bars), eight of which are
of PSC833 in patients with acute leukemia treated with cytarabine, within the NH 2 -proximal half of the protein. The second model (B), based
daunorubicin, and etoposide showed a modest benefit in patients on a comparison of human and murine MRP with other ATP-binding cas-
younger than 45 years of age, raising the potential of developing an sette transporters, suggests that there are up to four additional transmembrane
effective strategy in patients older than 60 years of age in whom PGP domains in the NH 2-proximal half of the protein. (Adapted from Loe DW, Deley
expression in leukemic cells is more common. Zosuquidar, a PGP RG, Cole SPC: Biology of the multidrug resistance-associated protein, MRP. Eur J
inhibitor, was tested for efficacy in a phase III trial by ECOG in 449 Cancer 32A:945, 1996.)