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Biomedical subjects

D F Hoth

Publications and source records attributed to D F Hoth.

At least 37 records · Page 2Linked to original sources
PubMed1988

2'-Deoxycoformycin (pentostatin) for lymphoid malignancies. Rational development of an active new drug.

A new antimetabolite, 2'-deoxycoformycin (pentostatin), has striking antitumor activity in several lymphoid neoplasms. Isolated from cultured soil organisms, this purine analogue is a potent inhibitor of adenosine deaminase (ADA), and is thus selectively toxic to lymphocytes. Early clinical trials showed that high doses of pentostatin caused severe and unpredictable toxicity, but responses in refractory lymphoid malignancies were encouraging. Careful pharmacologic studies led to the definition of a safe and effective low weekly dose, at which protracted ADA inhibition occurs in neoplastic cells. The most sensitive tumor identified is hairy cell leukemia, in which durable remissions are achieved in more than 90% of patients with a relatively brief course of treatment. Other responsive diseases include chronic lymphocytic leukemia, prolymphocytic leukemia, mycosis fungoides, and acute T-cell lymphoma or leukemia. Response has been seen in acute lymphocytic leukemia, but the higher doses required are substantially more toxic. Pentostatin is valuable for treatment of indolent lymphoid malignancies and may be useful in non-cancer-related lymphocyte research.

Adenosine Deaminase Inhibitors↗
PubMed1988

Deoxycoformycin: an active new drug for indolent lymphomas and hairy cell leukemia.

Promising results in the treatment of indolent lymphomas have been reported with the use of 2'deoxycoformycin. This antimetabolite, an adenosine deaminase inhibitor, also shows particular efficacy in hairy cell leukemia. Of 65 patients treated to date, 44 have achieved complete and lasting remission after a limited course of deoxycoformycin. While results are not as striking as those in hairy cell leukemia, deoxycoformycin may also be a valuable adjunct to alkylating agents in the treatment of CLL. The drug also is being studied in the treatment of mycosis fungoides and other lymphoid neoplasms. Side effects in all neoplasms are dose- and schedule-dependent.

Humans↗
PubMed1987

Role of thymidine in biochemical modulation: a review.

The role of thymidine in the treatment of cancer has been under clinical investigation for nearly a decade. Clinical trials have demonstrated that it lacks antitumor activity in its own right. In this review, the mechanism of action and rationale for the use of thymidine as a biochemical modulator of standard agents such as 5-fluorouracil, 1-beta-D-arabinofuranosylcytosine, and methotrexate are summarized. With this background, the clinical trials which have been conducted with thymidine, either alone or in combination, are described. We suggest a number of further studies of the role of thymidine in the biochemical modulation of antimetabolites.

Animals↗
PubMed1987

Arabinosyl-5-azacytosine: a novel nucleoside entering clinical trials.

Arabinosyl-5-azacytosine is a new compound which has been selected by the Division of Cancer Treatment, National Cancer Institute for clinical development as an antineoplastic agent based on its high degree of activity against a broad range of tumor types in preclinical studies. Therapeutic activity has been observed against murine and human leukemias, transplantable murine solid tumors, and human tumor xenografts. Arabinosyl-5-azacytosine exhibited a broader spectrum of activity against human solid tumors than cytosine arabinoside. Arabinosyl-5-azacytosine is phosphorylated to the nucleotide level by deoxycytidine kinase. Upon further anabolism to the triphosphate level, it can be incorporated into DNA. The mechanism of cytotoxicity is thought to be related to inhibition of DNA synthesis. Leukemic and solid tumor cell lines that are resistant to cytosine arabinoside due to deletion of deoxycytidine kinase activity are cross-resistant to arabinosyl-5-azacytosine. Unlike cytosine arabinoside, arabinosyl-5-azacytosine does not readily undergo deamination. Schedule dependence has been demonstrated in mice bearing L1210 leukemia, with superior activity seen with multiple doses administered on each treatment day compared to administration of larger but less frequently administered doses. From preliminary data in solid tumor models, however, antitumor activity did not appear to be superior with continuous infusion compared to that observed on a bolus schedule. Preclinical toxicology studies indicated that the bone marrow and gastrointestinal tract were the main target organs. A single large dose of arabinosyl-5-azacytosine could be tolerated by both mice and dogs. When administered as a continuous infusion, the toxicity was related to both the dose and duration of exposure, suggesting that toxicity resulted from a critical time above a threshold concentration as opposed to the total area under the concentration-time curve. Phase I clinical trials have been initiated to determine the maximum tolerated dose on a low dose continuous infusion schedule for 72 hours and also on a high dose short infusion daily times five schedule.

Antiviral Agents↗
PubMed1987

5-Methyltetrahydrohomofolate.

5-methyltetrahydrohomofolate was developed in the 1970's as an antifolate with the potential to overcome methotrexate resistance. This review summarizes the preclinical and clinical data which have accumulated to date. It is concluded that more recent, better characterized antifolates offer greater potential in achieving the goals for which this drug was introduced.

Animals↗
PubMed1987

Flavone acetic acid (LM 975, NSC 347512). A novel antitumor agent.

Flavone acetic acid (FAA) is a synthetic flavonoid compound which has recently begun clinical trials as an antitumor agent based on its striking activity in solid tumor model systems. The pharmacologic behavior of FAA in animals appears to be predictive of both its cytotoxic efficacy and its toxicity to normal tissues (principally the central nervous system and gastrointestinal tract). The design and conduct of phase I studies in man are based upon these principles, with the goal of maximizing their safety and efficacy.

Animals↗
PubMed1987

Trimetrexate: clinical development of a nonclassical antifolate.

Trimetrexate is a 2,4-diaminoquinazoline inhibitor of dihydrofolate reductase (DHFR) which is cytotoxic in vitro and in vivo to several tumors resistant to methotrexate. It is more lipophilic than the parent antifolate, and is not transported by the reduced folate carrier. These features promise activity greater than that of methotrexate in the clinic; its inability to undergo polyglutamylation may also enhance the therapeutic index. In preclinical models, the activity of trimetrexate was highly schedule dependent, being superior on repeated dose schedules. Phase I studies have demonstrated that myelosuppression is the major toxic effect of trimetrexate on all schedules tested in man. Phase II studies will evaluate a 5-day schedule initially; trials in multiple tumor types and examination of the role of schedule are already under way.

Animals↗
PubMed1987

Methodology for the rational development of methotrexate analogs in the clinic.

This paper suggests a development plan for antifolate analogs, based upon disease classifications that the National Cancer Institute has successfully utilized for the development of anthracycline and platinum analogs. Diseases are classified according to the role of the parent compound in standard therapy: 1) those in which methotrexate is an important component of standard treatment strategies that have state-of-the-art effectiveness; 2) those in which methotrexate has antitumor activity but no clear role in standard state-of-the-art treatment strategies; and 3) those in which methotrexate has insufficient activity to warrant its use alone or in combination. Developmental plans are specified for each of these disease classes. Trimetrexate is used as a specific example for these plans, although this method of drug development is equally applicable to other methotrexate analogs.

Antibiotics, Antineoplastic↗
PubMed1986

Central nervous system toxicity of fludarabine phosphate.

Fourteen patients developed severe central nervous system (CNS) toxicity after receiving an investigational antitumor agent, fludarabine phosphate (FAMP). The CNS toxicity has the distinctive features of delayed onset and progressive clinical course. Visual deficits were the most common presenting symptom and developed eventually in most cases. Deterioration of mental status and progressive encephalopathy were also observed. The development of clinical CNS toxicity appears dose-related; thirteen of 36 patients (36.1%) who received FAMP at high doses (greater than or equal to 96 mg/m2/day for 5-7 days per course) developed neurotoxicity, while only one of 443 patients (0.2%) who received the drug at low doses (less than or equal to 125 mg/m2 per course) developed similar toxicity. Although the precise mechanism responsible for this toxicity is yet unknown, progressive demyelination appears to be the responsible process. Extensive review of the clinical data failed to identify factors which might contribute to the development of CNS toxicity. Patients on trials of FAMP should be meticulously monitored for the possible development of neurotoxicity.

Acute Disease↗
PubMed1985

Effects of suramin on HTLV-III/LAV infection presenting as Kaposi's sarcoma or AIDS-related complex: clinical pharmacology and suppression of virus replication in vivo.

Suramin was given to ten outpatients with acquired immunodeficiency syndrome (AIDS) presenting as Kaposi's sarcoma (KS) or as an AIDS-related complex (ARC). Side-effects associated with the administration of 6.2 g of suramin over 5 weeks included fevers, rashes, urinary abnormalities, and transient rises in hepatic aminotransferases. Peak serum levels of over 100 micrograms/ml were attained. There was evidence of HTLV-III infectivity and replication in lymphocytes from four patients before therapy. The detectable virus level fell in each case by the time of the last dose, and in three cases it became undetectable at the end of therapy. In each case, viral replication was again detected in the weeks or months following the administration of suramin. Despite this in-vivo virustatic effect, no significant clinical or immunological improvement was observed using this short-term regimen. However, the results provide a rationale for investigating longer-term regimens.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Hypersensitivity reactions to amsacrine.

Five cases of hypersensitivity reactions to amsacrine are reported. These five cases are compared to the three cases previously published. Sixty-two reports on the clinical use of amsacrine in a variety of solid tumors and hematological malignancy were reviewed. Nine cases of hypersensitivity were described in the 2095 patients reported in these clinical trials. The approximate incidence of hypersensitivity to amsacrine is 0.4%.

Adolescent↗
PubMed1984

Anaphylactic reactions to diaziquone.

Diaziquone, an aziridinylbenzoquinone currently in phase II-III trials, is an alkylating agent, the major toxic effect of which is myelosuppression. We report here on six cases of hypersensitivity attributable to diaziquone. In five patients an acute reaction characterized by hypotension, bronchospasm, and urticaria was observed. In one patient a delayed urticarial rash was noted. Resolution was rapid in all patients but one, who responded to standard treatment over a period of hours. No reaction was fatal. Approximately 2000 patients have been treated with diaziquone in clinical trials sponsored by the National Cancer Institute. It is suggested that the reaction may not be to the drug itself but to the vehicle (dimethylacetamide) in which diaziquone is formulated. Studies to elucidate the relative contribution of drug and vehicle are warranted.

Aged↗