Michael A. Doukas

Phase I pharmacokinetic studies evaluating single and multiple doses of oral GW572016, a dual EGFR-ErbB2 inhibitor, in healthy subjects

GW572016 is a dual EGFR-ErbB2 inhibitor that has promise as an anticancer agent. Two phase I studies were conducted to determine the safety, tolerability and pharmacokinetics of single and multiple doses given to healthy subjects. The single dose study evaluated two groups of eight subjects in an ascending dose, 4-way cross-over, while the multiple dose study evaluated twenty-seven healthy volunteers in an ascending dose, double-blind, randomized, placebo-controlled, staggered parallel design. No serious adverse events were seen in either study. The most common adverse events for subjects receiving GW572016 were headache, diarrhea, rash, cold symptoms, gastrointestinal symptoms, and elevated LFTs, which were similar between treatment and placebo groups. Absorption of single doses of GW572016 was slightly delayed, with median tlag of 15 minutes (range 0–90 minutes) and achieved peak serum concentrations at a median of three hours (range 1.5–6 hours) post-dose. Serum concentrations after multiple doses of GW572016 demonstrated no significant accumulation at the 25 mg dose, and approximately 50% accumulation at the 100 mg and 175 mg doses, achieving steady state in six to seven days. A modest time-dependent increase in serum concentrations also was detected with multiple doses of GW572016. Single and multiple oral doses of GW572016 were well tolerated in healthy subjects, and resulted in dose-related systemic exposure of GW572016.

Acute Tumor Lysis Syndrome in Hematologic Malignancies

Acute tumor lysis syndrome (ATLS) represents one of the most urgent of all oncologic treatment related complications. This is due not only to its broad impact on organ dysfunction, but also to its relative ease of prevention and treatment when aware of its potential threat. Despite anecdotal experiences of ATLS in settings outside the use of chemotherapy, the majority of patients susceptible to ATLS can be predicted using clinical as well as laboratory parameters and prophylaxis can prevent this potentially lethal consequence of otherwise successful cancer therapeutics. This review article will attempt to bring the critical aspects involving ATLS together in order to delineate the pathophysiology as well as treatment of this generally avoidable entity.

Human immunodeficiency virus associated anemia

Anemia in HIV-infected patients is often overshadowed by other disorders associated with this viral disease, but it can markedly contribute to morbidity and limit antiviral therapy. Evaluation of this patient population is difficult because of the probability of a multifactorial etiology and spurious laboratory indicators. Ineffective or reduced erythropoiesis is a hallmark of most anemic HIV-infected patients, leading to usage and continuing research of recombinant hematopoietic cytokine therapy. The continuing explosion in knowledge of this virus, its effects, and treatment possibilities will, hopefully, lead to improved diagnostic and therapeutic options in approaching HIV-associated anemia.

Biochemical Modulation of 5-Fluorouacil Through Dihydropyrimidine Dehydrogenase Inhibition: a Southwest Oncology Group Phase II Trial of Eniluracil and 5-Fluorouracil in Advanced Resistant Colorectal Cancer

AbstractPurpose. To investigate thehypothesis that a systemic agent designedto inhibit dihydropyrimidine dehydrogenase(DPD), the first enzyme in thefluoropyrimidine degradative pathway, couldimprove the effective amount of5-fluorouracil (5-FU) delivered to a tumorresulting in enhanced response. Patients and methods. Eligibility includedcytologically or pathologically verifieddiagnosis of colorectal cancer thatrecurred during or within 12 months ofcompletion of adjuvant therapy,representing patients generally consideredresistant to fluorinated pyrimidinetherapy. Stratification was into twocohorts: recurrence while receivingadjuvant therapy, and relapse within 12months of completing adjuvant therapy.Treatment consisted of 28 days of oraltherapy every five weeks with eniluraciland 5-FU administered in a 10:1 ratio. Thedaily dose of eniluracil was 10 mg/m2with 5-FU 1 mg/m2, divided into twodoses. Results. Twenty-five patientsare evaluable for response: 9 relapsedduring therapy and 16 relapsed within oneyear of adjuvant therapy. In the firstgroup, there was one partial response (9%;95% CI 0–41%); in the second cohort therewas one confirmed complete response (5%;95% CI 0–23%) and one unconfirmed partialresponse, for an overall response rate of10%. Conclusions. This regimen lackssignificant activity in this targetpopulation. Pre-treatment intratumoral DPDexpression was not assessed, therefore themechanism of fluorinated pyrimidineresistance cannot be specificallyattributed to elevated DPD levels.Attempting restoration of chemotherapysensitivity through blockade of enzymes orsignal transduction molecules responsiblefor resistance is rational, provided thattumor target expression is the basis fortrial entry.

Diagnostic and clinical implications of lineage fidelity in acute leukemia patients undergoing allogeneic stem cell transplantation.

We report on a series of five acute leukemia patients who have undergone allogeneic bone marrow transplantation. Initially, these patients were classified as having biphenotypic leukemia; however, subsequent developments in the perception of what constitutes lineage fidelity has resulted in controversy regarding the diagnosis. Row cytometry and non-random cytogenetic results have had a major impact on redefining the concept of biphenotypic disease. In this report we review the diagnostic dilemma associated with defining acute leukemia linage fidelity as diagnostic techniques evolve. While our unique focus on the treatment of biphenotypic leukemia patients represents a small population, we verify the single most promising therapy where otherwise the diagnosis is dismal.