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Biomedical subjects

V Gandhi

Publications and source records attributed to V Gandhi.

At least 55 records · Page 3Linked to original sources
PubMed1995

Modulation of the cellular metabolism of cytarabine and fludarabine by granulocyte-colony-stimulating factor during therapy of acute myelogenous leukemia.

Previous in vitro investigations demonstrated that human leukemia cells, when incubated with hematopoietic growth factors such as granulocyte-colony-stimulating factor (G-CSF), augment the accumulation of the triphosphate 1-beta-D-arabinofuranosylcytosine (ara-C cytarabine). To test whether G-CSF infusion prior to ara-C infusion would biologically modulate the accumulation of ara-9-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) and other ara nucleotides in the leukemia blasts during therapy, protocols were designed to infuse G-CSF prior to fludarabine (9-beta-D-arabinofuranosyl-2-fluoroadenine monophosphate) and ara-C to increase the accumulation of the active triphosphates [9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate (F-ara-ATP) and ara-CTP] in acute myelogenous leukemia (AML) blasts during therapy. To complement these in vivo studies, ex vivo accumulation of ara-CTP was also investigated before and after G-CSF infusion. Patients (n = 5) treated on the fludarabine/ara-C/G-CSF regimen received a 30 mg/m2 dose of fludarabine followed by a 2 g/m2 dose of ara-C infused i.v. for 4 h. Beginning at 24 h, and every day, patients received a 6-h infusion of 400 microgram/m2 G-CSF. At 48 h, the fludarabine and ara-C couplet was repeated. Comparison of F-ara-ATP pharmacokinetics in circulating AML cells of patients on the fludarabine/ara- C/G-CSF regimen demonstrated that the area under concentration time curve (AUC) of F-ara-ATP increased significantly (median, 1.4-fold; range, 0.9-1.5; P = 0.045) after G-CSF infusion. This was due to an increased rate of F-ara-ATP accumulation by AML cells. The AUC of ara-CTP, on the other hand, was not affected (median, 1.0-fold; range, 1.0-1.2; P = 0.571) after G-CSF infusion. Because fludarabine potentiates the accumulation of ara-CTP, the effect of G-CSF on ara-CTP metabolism may not be evident in the AML blasts of patients on the fludarabine/ara-C/G-CSF regimen. To determine the effect of G-CSF when ara-C was infused alone, four additional patients were treated on a pilot protocol in which ara-C (2 g/m2) was infused on days 1 and 3 and G-CSF on day 2. The AUC of ara-CTP accumulation in these patients decreased by a median of 48% after G-CSF infusion. Consistent with these in vivo investigations, ex vivo ara-CTP accumulation was decreased in the AML blasts after G-CSF infusion. Based on these data it could be concluded that (a) infusion of G-CSF before fludarabine augmented the rate of F-ara-ATP synthesis in circulating AML blasts during therapy, suggesting that G-CSF may benefit fludarabine therapy by biological modulation; (b) G-CSF did not increase ara-CTP accumulation, rather it may have caused it to decrease; and (c) these data imply that when G-CSF and ara-C are used in combination, administration of fludarabine prior to ara-C may maintain the ara-CTP AUC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Combination of fludarabine and arabinosylcytosine for treatment of chronic lymphocytic leukemia: clinical efficacy and modulation of arabinosylcytosine pharmacology.

Previous studies have demonstrated that treatment with fludarabine 4 h prior to arabinosylcytosine (ara-C) potentiates the accumulation of the active triphosphate of ara-C (ara-CTP) in leukemic lymphocytes. The clinical efficacy of this combination was evaluated in 15 patients with chronic lymphocytic leukemia (CLL) that was advanced in their disease (median Rai stage, IV) and refractory to treatment with fludarabine. Patients received 0.5 g/m2 ara-C infused i.v. over 2 h followed at 20 h by a 30-min infusion of 30 mg/m2 fludarabine. At 24 h, an identical dose of ara-C was infused. To intensity the therapy and to determine the duration of fludarabine potentiation of ara-CTP accumulation, six additional patients with Rai stage III or IV CLL were treated with an amended 2-week protocol. On week 1, 30 mg/m2 fludarabine was infused over 30 min, followed 4 h later by a 2-h infusion of 0.5 g/m2 ara-C; on week 2, the fludarabine dose was followed 4 h later by a 4-h infusion of ara-C (1.0 g/m2). In all, 1 partial remission and 7 minor responses in 1 or more disease sites were observed in the 21 patients. The major treatment-related toxic effects were myelosuppression and infection. Comparison of the ara-CTP accumulation area under the concentration-time curve (AUC) in circulating CLL cells of patients on the amended protocol demonstrated a significant (P = 0.001) 1.6-fold (range, 1.4- to 2.0-fold) increase after fludarabine administration. Although the initial rates of ara-CTP accumulation were similar for the 2-h and 4-h infusions, ara-CTP accumulation continued for up to 4 h in four of five patients who received the longer infusion. The activity of the fludarabine and ara-C combination is being evaluated in in vitro model systems and in phase II clinical trials in combination with other drugs.

Adult↗
PubMed1994

Fludarabine--present status and future developments in chronic lymphocytic leukemia and lymphoma.

BACKGROUND: Fludarabine monophosphate (fludarabine) is an adenine nucleoside analogue active in indolent lymphoproliferative diseases which has an increasing role in studies incorporating combinations of agents which exploit biochemical modulation, inhibition of DNA repair, and radiosensitizing effects. PATIENTS AND METHODS: Patients with lymphoma and chronic lymphocytic leukemia (CLL) treated at the M. D. Anderson Cancer Center (MDACC) and reports in the literature form the basis of this report. RESULTS: CLL has traditionally been treated with alkylating agents and corticosteroids. In this study, fludarabine has shown marked cytoreductive ability in both previously treated patients and untreated patients. In the former group, there has been a 55% response rate in 374 patients, and 79% in the untreated CLL group. Fludarabine has also been very active in the management of low-grade lymphomas, with two-thirds of patients with follicular lymphoma and half of those with other indolent lymphomas responding. Waldenstrom's macroglobulinemia is also sensitive to the effects of fludarabine. Combination regimens were developed incorporating the substantial effectiveness of fludarabine and mitoxantrone where in the previously treated low-grade lymphoma group 25 of 28 patients (89%) responded. Fludarabine has the effect of increasing the triphosphate form of cytosine arabinoside in acute and chronic leukemic cells. This modulation has now been translated into therapy for acute leukemia and combined with cisplatinum in refractory CLL. Fludarabine inhibits DNA repair and enhances cross-linking of DNA by cisplatinum. The combination of fludarabine, ara-C, and cis-platinum is now being used in refractory CLL. Fludarabine is a radiation sensitizer, inhibiting repair of DNA damage. Studies are ongoing with this combination. CONCLUSIONS: Fludarabine is a potent molecule with a wide range of biochemical effects. Optimal use of this drug alone and in combination is continuing to be explored.

Adrenal Cortex Hormones↗
PubMed1994

Evolution of the arabinosides and the pharmacology of fludarabine.

An understanding of the pharmacokinetics of a drug is essential to the optimal design of the dose and schedule of chemotherapy protocols. As an extension, knowledge of the mechanism of drug action is necessary to construct the optimal strategy for combination chemotherapy. Nucleoside antimetabolites such as arabinosylcytosine, arabinosyladenine, and fludarabine are prodrugs that must enter cells and be phosphorylated to the respective triphosphates before they can elicit biological activity. DNA synthesis is the major metabolic target for this class of compounds. Common to members of the arabinosyl nucleoside class is the finding in experimental systems of a relationship between incorporation of each drug into DNA and the loss of clonogenicity. Although additional inhibitory mechanisms have been identified, they all require formation of the respective triphosphate. Thus, knowledge of the pharmacokinetics of the triphosphates in target cells and an understanding of the mechanisms by which these active forms of arabinosyl nucleosides kill cells are indispensable to the rational design of treatment protocols. This article considers the clinical development of arabinosyl nucleosides with respect to investigations of their pharmacokinetics and mechanisms of action. An understanding of these elements of arabinosyl nucleoside metabolism should provide a rationale for combinations with other chemotherapeutic agents and anticancer modalities.

Animals↗
PubMed1994

Fludarabine inhibits DNA replication: a rationale for its use in the treatment of acute leukemias.

Fludarabine is a prodrug that must enter cells and be phosphorylated to the nucleoside triphosphate, F-ara-ATP, to elicit biological activity. F-ara-ATP serves as an inhibitory alternative substrate in several key processes involved in DNA synthesis. The enzymes required in DNA synthesis and affected by F-ara-ATP are ribonucleotide reductase, DNA primase, DNA polymerases, 3'-5' exonuclease activity of DNA polymerases delta and epsilon, and DNA ligase I. The action of fludarabine on DNA replication provides a compelling rationale to use this agent for leukemias where target cells are actively synthesizing DNA, for example acute myelogenous leukemia. Additionally, the role of F-ara-ATP to potentiate the activity of deoxycytidine kinase makes it an appropriate candidate to use in combination with other nucleoside analogs which require deoxycytidine kinase for their activation. The present article reviews the effect of fludarabine on enzymes involved in DNA synthesis and the role of fludarabine in combination with arabinosylcytosine for the treatment of diseases other than indolent leukemias.

Acute Disease↗
PubMed1994

The expanding role of fludarabine in hematologic malignancies.

The major clinical experience with fludarabine has been obtained in patients with chronic lymphocytic leukemia (CLL). In the initial studies in previously treated patients with CLL, the complete and partial response rate (CR + PR) was over 50%, and in previously untreated patients with CLL, a CR + PR rate of 75-80% was noted with or without the addition of prednisone. Subsequent clinical trials have also demonstrated major activity with fludarabine in Waldenstrom's macroglobulinemia. Fludarabine was noted to be an active agent in indolent lymphoma in phase I/II studies. Approximately 60% of patients with follicular lymphoma respond to fludarabine when it is administered as a single agent. Many of these remissions are complete remissions despite patients having received extensive prior therapy. Combination programs are being developed for application in CLL and indolent lymphoma. Because of the activity of fludarabine in inhibiting DNA repair, it has been combined with cisplatinum and cytosine arabinoside and plans are in place to explore the radiation sensitizing effect of fludarabine in clinical trials. A combination of fludarabine plus ara-C is now being used in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) and a combination of fludarabine, ara-C, and G-CSF (FLAG) has been combined with idarubicin for the management of these conditions. Many of these activities of fludarabine are associated with its interaction with many enzymes which are important in DNA and RNA metabolism and in DNA repair. It is anticipated that these actions will be explored in a wider range of studies subsequently.

Antineoplastic Agents↗
PubMed1994

Effect of granulocyte-macrophage colony-stimulating factor on the metabolism of arabinosylcytosine triphosphate in blasts during therapy of patients with chronic myelogenous leukemia.

Because in vitro studies have indicated that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates arabinosylcytosine (ara-C) metabolism in leukemia blasts, we analyzed the pharmacokinetics of ara-C triphosphate (ara-CTP) in the blasts of patients with chronic myelogenous leukemia who were undergoing therapy with GM-CSF and ara-C. Patients received a 2-h infusion of 1.0 g/m2 ara-C followed by daily infusions of GM-CSF (125 micrograms/m2/day i.v. over 6 h) for 2-4 days. After the last GM-CSF infusion, a second, identical dose of ara-C was administered. The cellular pharmacokinetics of ara-CTP in circulating blasts were determined during and after each ara-C dose, and the area under the accumulation and elimination curve (AUC) measured over 12 h was compared before and after GM-CSF. Ara-CTP accumulation peaked within 1 h after the end of each ara-C infusion. Comparison of the AUC of ara-CTP before and after GM-CSF administration suggested that in the blasts of three of four patients, GM-CSF treatment decreased the ara-CTP AUC; the AUC values were altered only slightly in a fourth patient. Studies of these patients' blasts incubated in vitro with ara-C before and after clinical infusion of GM-CSF revealed similar ara-CTP accumulation patterns. Together, these studies suggest that 2-4 days of GM-CSF administration does not increase the accumulation of ara-CTP in the circulating blasts from patients in the blastic phase of chronic myelogenous leukemia.

Arabinofuranosylcytosine Triphosphate↗
PubMed1993

Fludarabine and cytosine arabinoside in the treatment of refractory or relapsed acute lymphocytic leukemia.

BACKGROUND: The objectives of the study were to evaluate the antileukemic efficacy and toxicity profiles of the combination of fludarabine and intermediate-dose cytosine arabinoside (ara-C) in refractory or relapsed adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS. Thirty adults with refractory or relapsed ALL were treated. Their median age was 45 years, 60% were in second or subsequent relapse, and 37% had Philadelphia chromosome-positive disease. Treatment consisted of ara-C 1 g/m2 during a period of 2 hours daily for 6 days, and fludarabine 30 mg/m2 during a period of 30 minutes daily for 5 days on days 2-6. Fludarabine was given 4 hours before ara-C to increase the rate of ara-C 5'-triphosphate (ara-CTP) accumulation in leukemic cells. Courses were repeated every 3 weeks or longer, depending on patient response and side effects. RESULTS: Nine (30%) patients achieved a complete remission (CR), 8 (27%) died during remission induction, and 13 (43%) had resistant disease. The median CR duration was 22 weeks, and the median survival was 12 weeks for all patients, and 34 weeks for those who had a response to treatment. Except for low platelet counts, which predicted shorter survival time, no other prognostic factors were demonstrated, considering the small number of patients treated. Myelosuppression-associated febrile episodes were the most common side effects, occurring in 28 (93%) patients. Neurotoxicity was noted in two (7%) patients. CONCLUSIONS: Fludarabine and ara-C are an active and relatively safe antileukemic combination in refractory or relapsed ALL. Future studies will incorporate other anti-ALL agents, such as topoisomerase II-reactive drugs, to improve the overall efficacy, and growth factors, to reduce myelosuppression-related complications.

Adult↗
PubMed1993

Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy.

PURPOSE: A protocol was designed to test the hypothesis that fludarabine infusion before arabinosylcytosine (cytarabine [ara-C]) would increase the accumulation of the active metabolite ara-C triphosphate (ara-CTP) in acute myelogenous leukemia (AML) blasts during therapy. PATIENTS AND METHODS: Patients (n = 5) received 1 g/m2 of ara-C infused intravenously (IV) for 2 hours, followed at 20 hours by 30 mg/m2 of fludarabine for 30 minutes. At 24 hours, another identical dose of ara-C was infused. To determine the optimal duration of ara-C infusion following fludarabine, five additional patients were treated on an amended protocol in which the ara-C infusion was extended to 3 g/m2 infused over 6 hours. RESULTS: Comparison of ara-CTP pharmacokinetics in circulating AML cells demonstrated that the area under the curve (AUC) of ara-CTP increased significantly (median, 1.8-fold; range, 1.6 to 2.4; P = .004) after fludarabine infusion. Neither the median plasma ara-C concentrations, the levels of its deamination product arabinosyluracil, nor the rate of ara-CTP elimination from circulating blasts was affected by fludarabine infusion. However, the rate of ara-CTP accumulation by AML cells was increased by a median of 2.0-fold (range, 1.8 to 2.2; P = .001) after fludarabine; the peak occurred within 1 hour of the end of the infusion. In vitro incubation of these cells with arabinosyl-2-fluoroadenine (F-ara-A) before ara-C also produced a median 1.7-fold increase in the ara-CTP accumulation rate. Pharmacology studies in patients receiving 6-hour infusions of ara-C demonstrated that the rate of ara-CTP accumulation was potentiated beyond 2 hours, but not for 6 hours. CONCLUSION: Infusion of fludarabine before ara-C augments the rate of ara-CTP synthesis in circulating AML blasts during therapy. Evaluation of 6-hour ara-C infusions demonstrated that potentiation of ara-CTP synthesis is maximal up to 4 hours in most patients; this pharmacologically optimized regimen should be considered for combination with other antileukemia drugs.

Adolescent↗
PubMed1993

Fludarabine for treatment of adult acute myelogenous leukemia.

The success of fludarabine as a single agent for therapy of chronic lymphocytic leukemia suggested its use in other leukemias such as adult acute myelogenous leukemia. Because doses that are tolerated in the clinic were not effective in the treatment of acute myelogenous leukemia, our approach was to combine low dose fludarabine with other active agents such as arabinosylcytosine (ara-C). This is also based on the rationale that fludarabine pretreatment modulates the metabolism of ara-C resulting in potentiation of the accumulation of its triphosphate. Improved response rates and clinical efficacy of this combination further suggested combining this couplet with DNA damaging agents, because the active triphosphates of both these analogs inhibit replication and repair processes of DNA synthesis.

Antineoplastic Agents↗
PubMed1993

Cellular pharmacology of fludarabine triphosphate in chronic lymphocytic leukemia cells during fludarabine therapy.

The pharmacology of fludarabine triphosphate (F-ara-ATP) in leukemic lymphocytes was studied during a phase II trial of fludarabine in 24 patients with chronic lymphocytic leukemia (CLL). Fludarabine was given as a 30-min i.v. infusion at a dose of 25 or 30 mg/m2 daily for 5 days. The concentrations of F-ara-ATP, the active metabolite of fludarabine, were determined in leukemic lymphocytes at intervals up to 24 hr after the first infusion. A median peak concentration of 19 microM (range, 6-52 microM) was generally reached 4 hr after the beginning of the infusion. No significant relationship was observed between clinical response and the median peak level of F-ara-ATP or the retention of F-ara-ATP in leukemic lymphocytes. In vitro incubation of CLL cells with the parent nucleoside of fludarabine, arabinosyl-2-fluoroadenine (F-ara-A), indicated that F-ara-ATP accumulated in a linear fashion in response to the product of the F-ara-A concentration times the duration of incubation. Exposing cells longer with lower F-ara-A concentrations or shorter with higher F-ara-A concentrations resulted in similar intracellular levels of F-ara-ATP as long as the products of fludarabine concentration and time of exposure were equal. These results and the fact that the fludarabine dose rate currently administered is well tolerated suggest that it may be the optimal dose rate for F-ara-ATP accumulation in CLL cells.

Adult↗
PubMed1993

Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia.

There is a strong association between ability of leukemia blasts to accumulate ara-CTP, the active metabolite of ara-C, and response to ara-C in patients with relapsed or refractory AML. Ara-C dose rates in excess of 0.5 g/m2/h do not produce further ara-CTP formation. In contrast, when given 4 h prior to ara-C at this dose rate, fludarabine, at doses that are free of neurotoxicity in CLL, enhances ara-CTP accumulation. This led us to administer fludarabine and ara-C to 59 patients with AML in relapse or unresponsive to initial therapy. Fludarabine was given at 30 mg/m2 once daily for 5 doses and ara-C at 0.5 g/m2/h for 2-6 h daily for 6 doses. Doses of fludarabine preceded those of ara-C by 4 h. Results with fludarabine and ara-C (FA) were compared with those of patients treated at M.D. Anderson with high-dose ara-C (HDAC) or intermediate-dose ara-C (IDAC). The complete remission rate with FA was 21/59 (36%) and the actuarial median CR duration 39 weeks. FA produced significantly higher remission rates than HDAC or IDAC in patients with initial remissions > 1 yr (14/20 vs 9/23 vs 6/18, p < 0.05). Response rates were similar for all three treatments in patients with initial remissions < 1 yr or with primary refractory disease. The regimen was well tolerated; one patient developed peripheral neuropathy. This low level of toxicity encourages combination with other antileukemia agents.

Adolescent↗
PubMed1993

Biochemical modulation of arabinosylcytosine for therapy of leukemias.

Analysis of different ribonucleotide reductase inhibitors to modulate arabinosylcytosine (ara-C) metabolism suggested that pretreatment with arabinosyl-2-fluoroadenine (F-ara-A) significantly potentiated the rate of ara-CTP (5'-triphosphate of ara-C) accumulation in both quiescent lymphocytes (p = 0.046) and in cycling blasts (p = 0.017). In vitro incubations of freshly isolated leukemia cells from patients with chronic (n = 7) or acute (n = 5) leukemias with F-ara-A, increased the rate of ara-CTP accumulation by a median of 1.5 or 1.7-fold, respectively, when subsequently incubated with ara-C. The objective of the present investigation was to test the hypothesis that ara-C can be biochemically modulated during therapy of leukemias. To test the biochemical modulation of ara-C in the clinical setting, we designed two protocols to administer fludarabine (clinical formulation of F-ara-A) and ara-C in a pharmacologically directed sequence for patients with chronic lymphocytic leukemia (CLL) refractory to conventional fludarabine therapy or for patients with acute myelogenous leukemia (AML) in relapse. Comparison of ara-CTP pharmacokinetics demonstrated a significant increase in the area under concentration curve (AUC) of ara-CTP both in CLL (median 1.5-fold) and AML cells (median 1.8-fold) after fludarabine infusion. Analyses of different processes involved in the metabolism of ara-CTP indicated that the increase in AUC was due to potentiation of the rate of ara-CTP accumulation. These studies demonstrate that protocols designed on biochemical and pharmacological rationales modulate ara-C metabolism during therapies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

New initiatives with fludarabine monophosphate in hematologic malignancies.

Fludarabine monophosphate (fludarabine) was initially discovered to have significant activity in indolent lymphoma and chronic lymphocytic leukemia (CLL). The major clinical experience with fludarabine is in previously treated patients with CLL. In such patients the complete and partial response rate (CR + PR) is over 50%. These results were obtained with 5-day schedules of fludarabine 25 to 30 mg/m2/d. Subsequent schedules have explored once-a-week fludarabine and a 3-day schedule every 4 weeks. These strategies, in particular the once-a-week schedule, have obtained inferior results. The addition of prednisone has not been associated with an improvement in response rate or survival. The application of fludarabine to previously untreated patients demonstrated a CR + PR rate of 75% to 80%. The addition of prednisone did not improve the response rate or survival in this group of patients. A significant concern in patients with CLL treated with fludarabine is a decrease in the CD4 and CD8 counts. Despite median posttreatment counts of approximately 200 CD4 lymphocytes/microL, the incidence of infections in patients in remission off therapy is low. Major clinical activity has been demonstrated with fludarabine in Waldenstrom's macroglobulinemia, in which more than one third of refractory patients achieve a CR or PR. Responding patients with anemia or thrombocytopenia have a marked improvement in blood counts. The duration of response has been long (> 30 months) in most responders. The early activity of fludarabine as a single agent in phase I/II studies in indolent lymphoma subsequently has been confirmed by a number of investigators. Fifty percent to 60% of patients with follicular lymphomas respond to fludarabine as a single agent. A number of these responses are complete despite the patients having received extensive prior treatment. A number of combination programs are being developed in CLL and indolent lymphoma. The combination of fludarabine with doxorubicin and prednisone has been developed and is being studied in phase I/II clinical trials. In addition, combinations of fludarabine and cytarabine with or without cisplatin based on elegant preclinical pharmacokinetic rationales have been applied to CLL with impressive cytoreductive activity but significant myelosuppression. A new combination of fludarabine, mitoxantrone, and dexamethasone has been developed for use in lymphoma. Phase I studies demonstrated a high response rate, especially in follicular lymphomas, with a number of patients achieving complete remission. Subsequent phase II studies demonstrate a response rate of 89% in patients with indolent lymphoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Antimetabolites, Antineoplastic↗
PubMed1993

Fludarabine: pharmacokinetics, mechanisms of action, and rationales for combination therapies.

Knowledge of the pharmacokinetics of a drug is essential to the optimal design of the dose and schedule of chemotherapy protocols. As an extension, an understanding of the mechanism of drug action is necessary to construct the optimal strategy for combination chemotherapy. Nucleoside antimetabolites such as fludarabine are pro-drugs that must enter cells and be phosphorylated to the nucleoside triphosphate before they can elicit biologic activity. Thus, knowledge of the pharmacokinetics of the triphosphate in target cells and an understanding of the mechanisms by which this active form of the drug act are indispensable to the rational design of treatment protocols. This article reviews the essential elements of the pharmacokinetics and mechanisms of action of fludarabine to provide a rationale for combinations of fludarabine with other chemotherapeutic agents and anti-cancer modalities.

Antineoplastic Agents↗