mitoguazone and Lymphoma--AIDS-Related

Methylglyoxalbisguanylhydrazone or MGBG is an agent with a unique mechanism of action (polyamine biosynthesis inhibition). MGBG was discarded in the 1960s because of severe mucositis and other toxicities. New clinical trials in the late 1970s and early 1980s utilized weekly administration and indicated MGBG had significant activity in patients with chemotherapy-refractory Hodgkin's and non-Hodgkin's lymphoma. In addition, some activity was noted in patients with head and neck, prostate, esophageal, and endometrial cancer. The toxicities on the weekly schedule were minimal and no myelosuppression was noted. Based on MGBG's spectrum of antitumor activity and its activity in severely debilitated patients, we hypothesize that MGBG may have greater antitumor activity in patients who are malnourished (possibly based on polyamine depletion). MGBG is a good candidate for treatment of AIDS-associated NHL because it has proven activity in patients with NHL which is not associated with AIDS, crosses the blood brain barrier, is non-myelosuppressive, and appears to work in patients with inanition (no polyamines available to reverse MGBG's antitumor effects). Clinical trials are ongoing to determine the activity of MGBG in AIDS-associated NHL and other diseases. Based on encouraging initial results, it appears MGBG may become part of our therapeutic armamentarium.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biogenic Polyamines; Hodgkin Disease; Humans; Lymphoma, AIDS-Related; Lymphoma, Non-Hodgkin; Male; Middle Aged; Mitoguazone

To evaluate the response and side effects of combination therapy with low dose CHOP chemotherapy and mitoguazone dihydrochloride in patients with non-Hodgkin's lymphoma associated with the acquired immunodeficiency syndrome (AIDS-NHL).. Eighteen patients newly diagnosed with intermediate or high-grade AIDS-NHL were treated with low dose CHOP as follows: day 1, cyclophosphamide 350 mg/m(2), intravenously (IV); doxorubicin 25mg/m(2) IV; vincristine 2mg IV; and prednisone 100mg given orally on days 1 through 5. In addition, mitoguazone dihydrochloride was given at a dose of 600 mg/m(2) IV on days 1 and 15 of each 28-day treatment cycle.. Seventeen males and one female patient were accrued. Twelve patients had high-grade pathologies while the remainder had an intermediate grade pathology (diffuse large cell). The median CD4+ lymphocyte count was 98/dl (range 1-924). Three patients (17%) reported an AIDS-defining illness prior to lymphoma diagnosis. Of 14 evaluable patients, 6 (43%) achieved a complete remission and 5 (35%) a partial remission. The median failure free and overall survival times were 6.5 and 8.4 months, respectively. Major toxicity was hematologic with grade 3 or 4 neutropenia in 72%; two patients died of neutropenic sepsis.. Mitoguazone in combination with low dose CHOP is a safe regimen, associated with a response rate of 79% (CR 43%, PR 36%, 95% CI=49-95%). These preliminary results suggest no major improvement in terms of response over use of CHOP without mitoguazone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Female; Humans; Lymphoma, AIDS-Related; Lymphoma, Non-Hodgkin; Male; Middle Aged; Mitoguazone; Prednisone; Vincristine

Patients with AIDS-related lymphoma usually have extensive lymphomatous disease, with relatively frequent involvement of the CNS. Approximately half may achieve complete remission after chemotherapy. Mitoguazone, an inhibitor of polyamine biosynthesis, has demonstrated efficacy in patients with de novo recurrent lymphoma. The drug is relatively nonmyelotoxic and may cross the blood-brain barrier. The current study was designed to assess the safety and potential efficacy of mitoguazone in patients with relapsed or refractory AIDS-lymphoma.. Thirty-five patients were accrued, all of whom had failed one (51%) or multiple (two to six) prior regimens. Mitoguazone (600 mg/m2) was given intravenously on days 1 and 8, and then every 2 weeks, until best response, progression, or toxicity.. The median age was 39 years. High-grade lymphoma was diagnosed in 29 patients (83%). Extranodal disease was present in 30 patients (86%), with multiple extranodal sites (two to seven) in 18 (51%). The median CD4 cell count at study entry was 66/dL (range, zero to 549). Twenty-six patients were assessable for response. The objective response rate was 23% (95% confidence interval [CI], 6.9 to 39.3), with complete remission in three patients (11.5%), and partial remission (PR) in three patients (11.5%). Six patients experienced stable disease. Median survival from study entry was 2.6 months for the group as a whole; 21.5 months (range, 3.8 to 29.1) in complete responders, 5.6 months (range, 3.8 to 34.8) in partial responders. The most common toxicities occurred solely during drug infusion and included vasodilation (63%), paresthesia (86%), and somnolence (17%). Fourteen patients (40%) experienced nausea and 16 (46%) vomiting (grade 3 in one). Ten patients (29%) developed stomatitis, including grade 3 in two and grade 4 in one. Seven patients (20%) developed neutropenia, with grade 4 in one. Thrombocytopenia occurred in nine patients (26%). While on study, three patients developed sepsis, four had pneumonia, and two developed opportunistic infections.. Mitoguazone is an effective agent in patients with multiply relapsed or refractory AIDS-related lymphoma, with acceptable toxicity. Further study in patients with newly diagnosed disease is warranted.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Lymphoma, AIDS-Related; Male; Middle Aged; Mitoguazone; Neutropenia; Recurrence; Remission Induction; Survival Analysis; Thrombocytopenia

Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m2 of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 micrograms/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m2 with a relatively large apparent volume of distribution at steady-state of 1012 l/m2 indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.

Topics: Adult; Antineoplastic Agents; Humans; Lymphoma, AIDS-Related; Male; Middle Aged; Mitoguazone

Discussions from a recent cancer conference held in May of 1995 are summarized in the following areas: 1) the effect of mitoguazone in relapsed non-Hodgkin's lymphoma; 2) the addition of ddI or ddC to chemo for advanced Kaposi's sarcoma (KS); 3) progress in use of three new anti-KS agents; 4) the effectiveness of phototherapy as palliation for KS; and 5) reasons why HIV prevalence is probably underestimated in women. Additionally, the paper reviews the Lymphoma Project Report which analyzed the epidemiology, pathogenesis, diagnosis, clinical manifestations, molecular characteristics, prognostic factors, and treatment of AIDS lymphoma. The following were among the findings: a regimen of doxorubicin, bleomycin, and vincristine with either ddI or ddC was well tolerated and evoked antitumor responses in patients with KS; 9-cis-retinoic acid and beta-human chorionic gonadotropin can induce remission of KS lesions; photodynamic therapy is an effective palliative therapy for some people with KS, but doses above 300 joules/cm2 result in scarring; and most American women who die of cervical cancer probably also have HIV infection according to a clinician from State University of New York in Brooklyn. The article concludes with a discussion of the differences between the focus of HIV research and HIV meetings for the ASCO assembly and the AIDS community.

Topics: Acquired Immunodeficiency Syndrome; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chorionic Gonadotropin; Female; Humans; Isotretinoin; Lymphoma, AIDS-Related; Lymphoma, Non-Hodgkin; Mitoguazone; Paclitaxel; Palliative Care; Photochemotherapy; Recurrence; Sarcoma, Kaposi; Uterine Cervical Neoplasms