Conventional Chemotherapeutic Treatment Research Articles

Herb–Drug Interactions in Oncology: Focus on Mechanisms of Induction

An increasing number of cancer patients are using complementary and alternative medicines (CAM) in combination with their conventional chemotherapeutic treatment. Considering the narrow therapeutic window of oncolytic drugs, this CAM use increases the risk of clinically relevant herb-anticancer drug interactions. Such a relevant interaction is that of St. John's wort with the anticancer drugs irinotecan and imatinib. It is, however, estimated that CAM-anticancer drug interactions are responsible for substantially more unexpected toxicities of chemotherapeutic drugs and possible undertreatment seen in cancer patients. Induction of drug-metabolizing enzymes and ATP-binding cassette drug transporters can be one of the mechanisms behind CAM-anticancer drug interactions. Induction will often lead to therapeutic failure because of lower plasma levels of the anticancer drugs, and will easily go unrecognized in cancer treatment, where therapeutic failure is common. Recently identified nuclear receptors, such as the pregnane X receptor, the constitutive androstane receptor, and the vitamin D-binding receptor, play an important role in the induction of metabolizing enzymes and drug transporters. This knowledge has already been an aid in the identification of some CAM probably capable of causing interactions with anticancer drugs: kava-kava, vitamin E, quercetin, ginseng, garlic, beta-carotene, and echinacea. Evidently, more research is necessary to prevent therapeutic failure and toxicity in cancer patients and to establish guidelines for CAM use.

The Role of Alemtuzumab in the Management of T-Cell Malignancies

T-cell malignancies are rare, making up 10% to 15% of all lymphoid neoplasms in adults. They include many different types of disorders such as T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, adult T-cell leukemia/lymphoma, cutaneous T-cell lymphoma, and peripheral T-cell lymphoma, which are themselves divided into multiple subcategories. Most T-cell malignancies arise as a result of chromosomal abnormalities, including T-cell receptor rearrangement anomalies. Viral infections are implicated in the development of adult T-cell leukemia/lymphoma and some cases of peripheral T-cell lymphoma have been linked to Epstein-Barr virus or human immunodeficiency virus infection. With the possible exception of T-cell large granular lymphocytic leukemia, which often has an indolent course, T-cell malignancies have not responded well to conventional chemotherapeutic treatment. The introduction of monoclonal antibodies for the treatment of cancer has changed the outlook for patients with T-cell malignancies. Recent studies with single-agent alemtuzumab, an anti-CD52 monoclonal antibody, have shown improved response rates and survival in patients with T-cell prolymphocytic leukemia and cutaneous T-cell lymphoma. Preliminary data also suggest that alemtuzumab may have activity in patients with heavily pretreated peripheral T-cell lymphoma who are refractory to conventional chemotherapy. Preclinical studies with mice bearing human adult T-cell leukemia/lymphoma cells suggest that alemtuzumab may have a potential therapeutic role in this setting. Treatment of T-cell hematologic malignancies with alemtuzumab appears promising. Earlier treatment and combination with chemotherapeutic agents may improve treatment outcome for patients with these malignancies and allow for consolidation with stem cell transplant strategies in selected patients.

Influence of prostaglandin A2 and 2-methoxyestradiol on mitogen-activated protein kinase (MAPK) expression levels in malignant cell lines

Mammalian cells often use the highly conserved mitogen-activated protein kinase (MAPK) or extracellular signal regulated protein kinase (ERK) cascades to transmit intracellular instructions. These signaling pathways have been proposed to regulate a diverse range of biological functions including apoptosis. Since 2-methoxyestradiol (2ME) and prostaglandin A2 (PGA2) play an active role in the induction of apoptosis, the influence of 1 μM 2ME or 20 μg/ml PGA2 was investigated on ERK1/2 expression levels in three cancer cell lines. PGA2 exposure led to a statistically significant increase in ERK1/2 expression levels of HeLa and WHCO3 cells. In contrast to the HeLa and WHCO3 cancer cell lines, no effect on ERK1/2 expression levels was observed after exposure of PGA2 to MCF-7 cells. 2ME caused a statistically significant increase in ERK1/2 expression levels in HeLa, MCF-7 and WHCO3 cells. WHCO3 cells were shown to be more susceptible to the effects of PGA2 and 2ME compared to the other two cancer cell lines. Since the characteristics of both PGA2 and 2ME render them as possible anti-tumor agents when compared to conventional chemotherapeutic treatments, understanding the functional role of signaling events and their regulation by interfering pathways after exposure of cells to PGA2 and 2ME respectively, will provide new insights into mechanisms involved in malignant cell proliferation.

Antibody-targeted chemotherapy of acute myeloid leukemia using gemtuzumab ozogamicin (Mylotarg)

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and accounts for 20% of pediatric leukemia. Although conventional chemotherapy induces clinical remissions in most patients with AML, recurrent leukemia represents the major obstacle to cure. Conventional chemotherapy reinduction is associated with limited efficacy and substantial toxicity. Chemotherapy specifically targeted to leukemic cells by monoclonal antibodies might enable patients to achieve remissions more safely than conventional approaches. After evaluating a series of phase II studies, the U.S. Food and Drug Administration approved Mylotarg (gemtuzumab ozogamicin) for the treatment of patients with CD33-positive AML in first relapse who are 60 years of age or older and who are not considered candidates for other types of cytotoxic chemotherapy. Among 277 adult patients with CD33-positive AML in first relapse, 26% experienced an overall response after Mylotarg monotherapy. Despite the fact that myelosuppression, hyperbilirubinemia, and elevated hepatic transaminases were commonly observed, the incidences of severe infections and mucositis were relatively low in comparison with conventional chemotherapeutic treatment. Preliminary reports in pediatric patients also report Mylotarg to be reasonably well tolerated. Recently, data from study regimens combining Mylotarg and conventional chemotherapy suggest an unusually high remission induction rate in de novo AML patients. Information assembled from prospective, ongoing studies in the United States and the United Kingdom should help us use this novel immunoconjugate in a safe and effective manner.

Costs of toxicity during chemotherapy with CHOP, COP/CVP, and fludarabine

The costs of chemotherapy toxicity were analyzed in patients with relapsed low-grade non-Hodgkin's lymphoma (NHL). A total of 91 specialists regularly treating NHL were interviewed by telephone to identify the most commonly used treatment regimens. Retrospective case record forms providing data on 424 patients with relapsed low-grade NHL were used to assess adverse event (AE) frequency and management. Data on one cycle of treatment was collected for each patient, and unit costs were assessed and extrapolated for six cycles to estimate AE costs for an average course of treatment. Average AE management costs were evaluated by country and treatment regimen. Toxicity costs were substantial for the most commonly used chemotherapy regimens, namely CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), COP/CVP (cyclophosphamide, vincristine, prednisone), and fludarabine therapies. In Canada CHOP-associated AEs costs (EUR 5.036 per patient) were more than twofold greater than drug acquisition costs, and cost more than AEs associated with COP/CVP (EUR 3.252) or fludarabine (EUR 1.273). In Germany CHOP-associated AE costs (EUR 2.515) were comparable to to those associated with COP/CVP (EUR 2.658). In Italy CHOP-associated AE costs (EUR 2.179) were considerably less than those associated with fludarabine treatment (EUR 4.908). Neutropenia and fever/infection AEs were the most common and more expensive to treat than nausea and vomiting, anaemia, thrombocytopenia, or other AEs in all three countries. This study shows that management of neutropenia and fever/infection are the most expensive AE costs associated with conventional chemotherapeutic treatment of relapsed low-grade NHL. AE management costs are substantial and are likely to be an important cost driver in all countries.

Mylotarg: antibody-targeted chemotherapy comes of age.

Mylotarg (gemtuzumab ozogamicin, CMA-676; Wyeth-Ayerst Laboratories, Philadelphia, PA) recently was approved by the US Food and Drug Administration for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse, age 60 years or older, who are not considered candidates for other types of cytotoxic chemotherapy. In combined phase II studies of 142 patients with CD33-positive acute myeloid leukemia in first relapse, Mylotarg monotherapy was associated with a 30% overall response rate. Although treated patients had relatively high incidences of myelosuppression, hyperbilirubinemia, and elevated hepatic transaminases, the incidences of severe mucositis and infections were low compared with what might be expected in association with conventional chemotherapeutic treatment. Preliminary data in pediatric patients also suggest that the immunoconjugate is reasonably well tolerated. Studies of Mylotarg in combination with anthracycline, cytarabine, and agents that inhibit P-glycoprotein are underway.

Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukaemia in first relapse

Gemtuzumab ozogamicin (CMA-676, Mylotarg®), an antibody-targeted chemotherapy agent, was recently approved by the FDA for the treatment of patients with CD33+ acute myeloid leukaemia (AML) in first relapse who are 60 years of age or older and who are not considered candidates for other types of cytotoxic chemotherapy. In combined Phase II studies of 142 patients with CD33+ AML in first relapse, gemtuzumab ozogamicin monotherapy was associated with a 30% overall response rate. While treated patients had relatively high incidences of myelosuppression, grade 3 or grade 4 hyperbilirubinaemia (23%) and elevated hepatic transaminases (17%), the incidences of grade 3 or grade 4 mucositis (4%) and infections (28%) were low compared with what might be expected in association with conventional chemotherapeutic treatment. In contrast with the usual in-patient administration of cytarabine and anthracycline-containing induction regimens, a large number of patients were treated with gemtuzumab ozogamicin as outpatients (38% and 41% for the first and second doses, respectively). Two prognostic factors for patients with AML in first relapse, age and duration of complete remission, had relatively little effect on response rates to gemtuzumab ozogamicin. Preliminary data in pediatric patients also suggest the immunoconjugate to be reasonably well tolerated. Studies of gemtuzumab ozogamicin in combination with anthracycline and cytarabine are underway. Gemtuzumab ozogamicin, administered to patients with CD33+ AML in first relapse, has shown overall response rates comparable to conventional agents and a safety profile that appears to be favourable.

Clinical studies of new "biologic" approaches to therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates.

Conventional chemotherapeutic treatments of acute leukemias are often associated with life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target antigens on leukemic blasts are being explored for their antileukemic effects and as a means of delivering chemotherapy or radiation directly to malignant cells. This approach might be safer and more effective than current non-specific chemotherapeutic agents. The cell surface antigens CD33 and CD45 are attractive targets. Although CD33 is expressed on acute myelocytic leukemic blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all non-hematopoietic tissues. Anti-CD33 antibodies have been engineered to selectively target malignant myeloid and immature normal cells while sparing normal stem cells. Recently, anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. The strategy for using CD45 as a target differs from CD33 in that it is expressed not only by the vast majority of leukemias, but also by normal stem cells. Therefore, 131I-labeled anti-CD45 antibody has been used in combination with conventional preparative regimens for patients receiving marrow transplantation for acute leukemia. Because the receptor for granulocyte-macrophage colony-stimulating factor is expressed by most myeloid leukemias, fusion proteins consisting of granulocyte-macrophage colony-stimulating factor ligand associated with diphtheria toxin have been proposed as a means of delivering a toxic agent directly to leukemic cells. Both unconjugated and conjugated antibodies show significant promise in the treatment of acute myelocytic leukemia.

Regulation of CD95 expression and CD95-mediated cell death by interferon-gamma in acute lymphoblastic leukemia with chromosomal translocation t(4;11).

The regulatory effects of IFNgamma on CD95 expression and CD95-mediated cell death were investigated in three high-risk pro-B acute lymphoblastic leukemia (ALL) lines that carry the chromosomal translocation t(4;11)(q21;q23). These leukemias are characteristically refractory to conventional chemotherapeutic treatments operating through the induction of apoptosis. However, the mechanisms leading to increased cell survival and resistance to cell death in these leukemias are largely unknown. Interferon-gamma (IFNgamma), a potent inhibitor of hematopoiesis, acts in part by upregulating CD95 and sensitizing cells to CD95-induced apoptosis. The t(4;11) lines SEM, RS4;11, and MV4;11 expressed low levels of CD95, but were completely resistant to CD95-mediated death. Addition of IFNgamma markedly upregulated CD95 expression in SEM (8-9-fold), RS4;11 (2-3-fold), and MV4;11 (2-3-fold) lines. However, after treatment with IFNgamma, only an 11% increase in sensitivity to CD95-mediated cell death was observed in SEM cells, whereas RS4;11 and MV4;11 cells remained resistant. Cycloheximide, but not actinomycin D or brefeldin A, increased CD95-specific cell death only in IFNgamma-treated RS4;11 cells by approximately 12%. Abundant levels of Bcl-2 and Bcl-XL, known to inhibit CD95-signaling in some cells, were present suggesting a possible role for both molecules in the resistance to CD95-mediated cell death. Resistance of the leukemic blasts to CD95-mediated cell death and the failure of IFNgamma to substantially sensitize the CD95-signaling pathway may contribute to the highly malignant phenotype of pro-B ALL with translocation t(4;11).

Differential induction of cell death in human glioma cell lines by sodium nitroprusside.

High grade gliomas represent very aggressive and lethal forms of human cancer, which often exhibit recurrence after surgical intervention and resistance to conventional chemotherapeutic and radiologic treatment. The clinically approved antihypertensive agent sodium nitroprusside (SNP) has been shown to induce cytotoxicity toward a number of carcinoma cell lines in vitro. Three human glioma cell lines were examined for susceptibility to the cytotoxic effects of SNP. The role of the protein kinase C (PKC)alpha gene in mediating resistance to SNP-induced killing in U343 cells was investigated using antisense oligonucleotide inhibition. Stable transfection and overexpression of the PKCalpha gene in the SNP-susceptible cell line U251 was performed to further implicate PKCalpha as a mediating factor in SNP cytotoxicity. In addition, the presence of bcl-2 protein in these cells was examined for possible correlation(s) with resistance to SNP. Exposure of U251 cells and LN-Z308 cells to 0.5 mM SNP resulted in significant cytotoxicity over a 72-hour period. U343 cells were resistant to SNP killing. U343 cells were shown to exhibit higher basal levels of PKCalpha and bcl-2 than either U251 or LN-Z308 cells. bcl-2 expression and resistance to SNP toxicity both were decreased by the introduction of PKCalpha antisense oligonucleotides into U343 cells. Conversely, enhanced PKC activity in PKCalpha-transfected U251 clones was associated with increased bcl-2 expression and greater resistance to SNP-induced toxicity relative to control transfected cells. SNP can induce cytotoxicity in glioma cells. The susceptibility of these glioma cells to nitroprusside-induced killing appears to be correlated inversely with bcl-2 and PKC activity. bcl-2 levels in these cells can be altered through modulation of PKC signaling, specifically, by induction or inhibition of PKCalpha. These in vitro results provide an interesting basis for further study into the potential use of SNP for treatment of human gliomas in patients receiving combination therapy with conventional chemotherapeutic agents that exhibit PKC inhibitory activity.