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Background & Objective: Treatment of relapsed or refractory non-Hodgkin's lymphoma (NHL) remains problematic with no standard salvage chemotherapy regimen. This study was to evaluate the efficacy of MINE (mitoxantrone, mesna/ifosfamide and etoposide) regimen on relapsed or refractory NHL, and observe its toxicity., Methods: Records of 38 patients with relapsed or refractory invasive NHL, treated with MINE regimen from Jan. 2001 to Jun. 2003, were reviewed. All patients had received at least 1 type of chemotherapy regimen (median, 2 types; range, 1-4 types) with a median of 6 chemotherapy cycles (range, 2-12 cycles). The patients received a median of 4 cycles (range, 2-6 cycles) of MINE regimen., Results: The treatment outcome and adverse events of all patients were assessable. The overall response rate was 47.4%, with a complete response (CR) rate of 15.8%. The response rates were 57.7% in the 26 patients with B-cell lymphoma and 25.0% in the 12 patients with T-cell lymphoma. The 1- and 2-year survival rates were 34.2% and 7.9%, respectively. The major adverse event was myelosuppression: the prevalence of grade III-IV neutropenia was 39.5%, and that of grade III-IV thrombocytopenia was 13.1%. One patient suffered grade III liver toxicity., Conclusions: MINE regimen was effective for patients with relapsed or refractory invasive NHL, and its toxicity is well tolerated, but the response term is relatively short. Further clinical study on the application of MINE regimen is warranted.

Background: Drug-induced panniculitis are uncommon. We report the second case of panniculitis induced by MINE chemotherapy., Case Report: A 31-year-old woman with relapsed Hodgkin disease was treated with MINE cytostatic regimen. Multiple erythematous and painful nodules of panniculitis developed on her chest, abdomen and thighs fifteen days after the beginning of drug administration with a second flare up after second administration of the same drugs. The eruption cleared slowly after treatment withdrawal., Discussion: To our knowledge, our case is the second reported case of panniculitis induced by MINE chemotherapy. Drug-induced panniculitis is uncommon and usually induced by steroid treatment. Some cases of panniculitis induced by atenolol, potassium bromide, apomorphine, interferon alpha and interleukin 2 have been described. Few cutaneous adverse effects are reported with MINE chemotherapy: rash, erythema and swelling of extremities. A case of inflammatory swelling of thighs with hemorrhagic panniculitis due to this treatment has been described recently.

The pharmacology and clinical application of three guanidino-containing compounds are reviewed in this commentary with special focus on a new member of this group of drugs, CHS 828 [N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N"-4-pyridylguanidine]. m-Iodobenzylguanidine (MIBG) and methylglyoxal bis(guanylhydrazone) (MGBG) have been extensively studied, preclinically as well as clinically, and have established use as anticancer agents. MIBG has structural similarities to the neurotransmitter, norepinephrine, and MGBG is a structural analog of the natural polyamine spermidine. CHS 828 is a pyridyl cyanoguanidine newly recognized as having cytotoxic effects when screening antihypertensive compounds. Apart from having the guanidino groups in common, there are many differences between these drugs in both structure and their mechanisms of action. However, they all inhibit mitochondrial function, a seemingly unique feature among chemotherapeutic drugs. In vitro in various cell lines and primary cultures of patient tumor cells and in vivo in various tumor models, CHS 828 has cytotoxic properties unlike any of the standard cytotoxic drugs with which it has been compared. Among these are non-cross-resistance to standard drugs and pronounced activity in tumor models acknowledged to be highly drug-resistant. Similar to MIBG, CHS 828 induces an early increase in extracellular acidification, due to stimulation of the glycolytic flux. Furthermore, ATP levels decrease, and the syntheses of DNA and protein are shut off after approximately 30 hr of exposure, indicating active cell death. CHS 828 is now in early clinical trials, the results of which are eagerly awaited.

Background: The MINE regimen (mitoguazone, ifosfamide, vinorelbine and etoposide) is a salvage chemotherapy for relapsed and refractory Hodgkin's disease., Case Reports: We report the cases of a 16-year-old girl and a 17-year-old boy who had Hodgkin's disease and developed painful and massive subcutaneous inflammatory edema after MINE chemotherapy. Morphine was unable to control pain leading to major functional disability of joint movement. One patient had an elevated creatine kinase level, hypoalbuminemia, hypodermic and muscular edema at magnetic resonance imaging and diffuse hemorrhagic hypodermic edema at skin biopsy. The other patient was found to have only hypoalbuminemia. The clinical course was favorable in both cases within a few weeks, but with recurrent episodes of pain and localized areas of fat necrosis five months later in one case., Discussion: This side effect of MINE chemotherapy - subcutaneous inflammatory edema, myalgia and skin pain - has not been described previously for the different components of the regimen. Three clinicopathological hypotheses could be put forward: capillary leak syndrome, panniculitis, toxic fasciitis. The causal drug remains undetermined, but the most likely would be vinorelbine because of the chronology of the eruptions during the first and last days of chemotherapy and because of the known vascular toxicity of vinorelbine which could explain a capillary leak syndrome.

Mitoguazone, an investigational agent with significant activity in advanced lymphoma, was added to a modified CHOP regimen (COPA) in an effort to improve the activity of standard therapy in 66 previously untreated patients with stages II-IV lymphoma and diffuse histology of intermediate or high grade other than lymphoblastic in this phase II pilot study. The regimen was well tolerated and the complete response rate in diffuse large cell lymphoma was 55%. Sixty-five percent of all complete responders were in complete response for at least one year. Despite these excellent results. it is unlikely that the addition of mitoguazone improved results compared with those obtained with standard therapy alone, since similar results have been frequently reported with the latter.

Purpose: 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., Patients and Methods: 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., Results: 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., Conclusion: 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.

Fifty-one patients with primary refractory or relapsed malignant lymphoma (47 non-Hodgkin's lymphoma and four Hodgkin's disease) were treated with a new chemotherapeutic regimen (cisplatinum, methyl GAG, bleomocyin, methyl prednisolon). Among these 51 patients, 41 had measurable disease. Three of these 41 patients achieved complete remissions (7.3%) and 17 showed partial response (41.5%). The low hematological toxicity of this chemotherapeutic combination allowed us to give the full dose at the planned cycle date in 90% of the cycles. No major toxicity were observed (two minor neurological toxicities, one ototoxicity associated with oral mucositis toxicity, 6 febrile episodes) during 164 courses. With a median follow-up of 12 months, 18% of patients were alive without disease. We conclude that in this particular population of malignant lymphomas, Cis-BMP is an effective therapy with minimal toxicity.

Seventy-two patients with recurrent or refractory malignant lymphoproliferative diseases were treated with MIME combination chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) and concurrent mesna to prevent urothelial toxicity; 41 patients had high/intermediate-grade non-Hodgkin's lymphoma (NHL), 18 low-grade NHL/chronic lymphocytic leukemia (CLL), and 13 Hodgkin's disease (HD). The overall response rates were 56% in high/intermediate-grade NHL, 11% in low-grade NHL/CLL, and 69% in HD respectively. Median survival in the same 3 groups was 7, 2 and 10 months respectively. Neither previous type of response to chemotherapy nor previous amount of treatment predicted the outcome of MIME chemotherapy. Toxicity was modest, hemorrhagic cystitis did not occur, and only one therapy-related death occurred. Although MIME appears to be a safe treatment with considerable activity in recurrent or refractory lymphoproliferative disease very few patients become long-term survivors. However, MIME is well suited for remission induction in patients intended for subsequent autologous bone-marrow transplantation.

Twenty patients with refractory multiple myeloma were treated with methylglyoxal-bis(guanylhydrazone) (MGBG), an inhibitor of polyamine synthesis. MGBG 500 mg/m2 was administered on days 1 and 8, and then every 14 days. The dose was escalated to 600 mg/m2 on day 22, as tolerated. Of 14 evaluable patients, none met ECOG criteria for an objective response. The major toxicity was hematologic and related infections. MGBG demonstrated insufficient activity in the treatment of refractory multiple myeloma to warrant further study.

Thirty adult patients with relapsed or refractory malignant lymphoma underwent a Phase I-II trial of salvage chemotherapy combining methyl-gag, high-dose Ara-C, M-Amsa, and ifosfamide (MAMI protocol). All patients had been extensively pretreated. At the time of salvage therapy, 21 patients had visceral involvement and 23 patients were refractory. The overall response rate was 50% (11 patients in complete remission and 3 patients in partial remission). The main toxicity was myelosuppression; 4 treatment-related deaths occurred and 17 patients died of tumor progression with a median of 5 months. The MAMI protocol showed similar antitumoral efficacy to that of other salvage chemotherapy regimens used for poor prognosis malignant lymphoma but was more toxic. However, a response rate of 45% in refractory patients should be taken into account and this drug association deserves further investigation with regard to the selection of patients for bone marrow transplants.

Ten patients with AML refractory to anthracyclines and cytosine arabinoside were treated with vincristine 1.4 mg/m2 and methotrexate (MTX) 2.5 gm/m2 by intravenous (IV) bolus on day 1 [citrovorum factor (CF) rescue began 24 h later], BCNU 80 mg/m2, and cyclophosphamide 900 mg/m2 IV 36 h after MTX and MGBG 300 mg/m2 IV over 1-2 h on days 3, 4, and 5. Bone marrow aplasia was achieved in all patients by day 12. Five patients (50%) achieved complete remission (CR). Two patients died of sepsis during induction. The median duration of remission was 24 weeks (range 8-38). Maintenance therapy was employed in three patients (high-dose MTX-CF in 2 and MGBG plus BCNU in 1), but did not appear to significantly increase the duration of remission. Nausea and vomiting occurred in eight patients. Five patients developed moderate stomatitis and one developed a moderately severe cutaneous reaction. This pilot experience demonstrates that patients with refractory AML can achieve CR after aggressive treatment with so-called second-line drugs. and may indicate that collateral sensitivity to MTX exists in cells which have become resistant to anthracyclines, a situation we previously described in an experimental cell line.

Twenty-four patients with epidermoid carcinoma of the esophagus have been treated, in a phase II trial, with methyl-GAG using a weekly schedule. Eighteen patients had received prior chemotherapy with cisplatin-containing combinations. Of 23 evaluable patients, four (17%) had partial remissions, each lasting 2 months. All patients had received prior chemotherapy. Toxic effects were manageable and included mild nausea and vomiting, mucositis, and fatigue. Using this schedule, methyl-GAG had modest activity in esophageal cancer, with acceptable toxicity. Its role in combination chemotherapy remains to be defined.

Methylglyoxal-bis(guanylhydrazone) (MGBG), an inhibitor of polyamine synthesis, was administered to 35 patients with hormone-resistant advanced adenocarcinoma of the prostate in doses of 500 or 600 mg/m2 per week intravenously. Of 31 patients with bidimensional measurable soft-tissue lesions, 25 had an adequate trial, defined as four or more doses. Six (24%; 95% confidence limits, 8% to 32%) patients achieved a partial remission (greater than or equal to 50% reduction in tumor size) in soft-tissue disease. Response was noted to start after one to two doses and persisted for a median of three months (range, 1 to 4 months). Toxicity was tolerable, and significant myelosuppression was not observed. The lack of response in osseous metastases may be secondary to the short duration of remission or to the presence or inducibility of the enzyme ornithine decarboxylase in bone. Since some animal prostatic cancer tumor models are sensitive to cytotoxic drugs that produce polyamine inhibition, clinical trials of MGBG combined with other inhibitors of the polyamine pathway should be explored.

We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl-GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma.

alpha-Difluoromethylornithine (DFMO) is a potent inhibitor of the synthesis of putrescine (pu) and spermidine (sd) in some benign and malignant tissues. Intracellular deprivation of pu and sd has been shown to induce an enhanced uptake of polyamine-analogs such as methyl-GAG (MGBG). The purpose of this study was to investigate the tolerance and the toxicity of the combination of DFMO and MGBG. Thirty-six patients received 4 X 2 g of DFMO/day orally and every 2 weeks 250-500 mg/m2 of MGBG as a 2-hr infusion, starting on day 14. Besides the well known acute and late side-effects of methyl-GAG, dose-limiting toxicity consisted also of thrombocytopenia, leucopenia, dyspnea, hemolysis and jaundice. The maximal tolerated dose of MGBG for one course was 350 mg/m2 and for repeated courses 250 mg/m2, due to cumulative toxicity. Furthermore, after 8 weeks of continuous administration of DFMO 70% of the patients had a severe hearing loss, which was reversible after a treatment delay of 4-6 weeks. Since the hearing loss prohibited the continuous use of DFMO, two different schedules of intermittent DFMO-administration together with two different infusion periods of MGBG have been investigated in 15 patients. In none of these patients did hearing loss occur. The schedule of continuous administration of 4 X 2 g of DFMO/day orally for 21 days and 250 mg/m2 of MGBG as a 24-hr infusion on days 7, 14 and 21, repeated on day 42, was tolerated best. In 28 evaluable patients two partial remissions were seen. Pretreatment with DFMO significantly enhanced the toxicity of MGBG and the combination of both drugs produced side-effects not seen with either drug alone.

Broad phase II trial of methylglyoxal-bi (guanylhydrazone) (MGBG) is under way at the Memorial Sloan-Kettering Cancer Center. Studies in renal cell carcinoma, lymphomas, and non-small-cell lung cancer are completed, and substantial numbers of patients with esophageal and head and neck cancer have been treated. Small numbers of patients with other solid tumors have also been entered into the study. MGBG has significant antineoplastic activity against lymphomas, with 16/40 heavily pretreated patients (40%) having partial remissions (PR) lasting 1 to 8+ months. MGBG has also demonstrated more modest activity in non-small-cell lung cancer, esophageal, and head and neck carcinoma; it appears to have little or no therapeutic value in renal cell cancer. Toxicities have been manageable, and included mild nausea and vomiting, diarrhea, mucositis, and myelosuppression. The dose-limiting toxicity, seen most frequently in those patients with impaired renal function, was lethargy and fatigue. MGBG has demonstrated activity in lymphomas, lung, esophageal, and head and neck cancer. Further trials of this agent are indicated, both alone and in combination.

The Southwest Oncology Group has evaluated methyl-GAG on a weekly schedule among patients with lymphoma and Hodgkin's disease. Among 56 fully and partially evaluable patients responses were seen in 3 of 10 patients with Hodgkin's disease and 11 of 46 patients with lymphoma. Toxicity was acceptable. Methyl-GAG has significant antitumor activity among this group of heavily pretreated patients. Additional trials of methyl-GAG in combination with other agents are underway.

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. Moreover, current results indicate that MGBG has useful antitumor activity in patients with advanced malignant lymphoma and carcinomas of the head and neck, esophagus, and lung (non-small cell). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs. Furthermore, Phase II and Phase III evaluation are required to determine the therapeutic potential of this unique agent.

A phase II trial of combination chemotherapy with mitoxantrone, cisplatin, and methyl-glyoxal bix-guanylhydrazone (MGBG) was conducted in 32 patients with unfavorable histology malignant lymphoma. All patients had relapsed after only one prior chemotherapy regimen (CHOP--56%; mBACOD--28%). There were three complete and eight partial responses (overall response rate--34%) among 32 eligible patients. The median duration of remission was 6.0 months. Severe granulocytopenia was common, with 19/32 patients (63%) suffering life-threatening, and 1/32 (3%) suffering fatal, granulocytopenia. We conclude that mitoxantrone-cisplatin-MGBG has modest activity as salvage treatment in malignant lymphoma patients, but produces severe toxicity.

Methyl-GAG, a polyamine synthesis inhibitor, was prospectively evaluated in the treatment of advanced renal adenocarcinoma. Twenty-five patients with measurable disease received methyl-GAG weekly at a starting dose of 500 mg/m2 iv, with dose escalation by 50 mg/m2/week (maximum dose, 825). All 25 patients are evaluable for response. Four of these patients (16%) achieved responses including three partial responses and one complete response, with a median duration of 9 weeks (range, 4--15). Nine patients (36%) remained stable and 12 (48%) had progressive disease. In the four responders, regression of disease occurred within the first 4 weeks of therapy. Toxic effects were generally mild and included nausea or vomiting (68%), myalgia (44%), mucositis (40%), neuralgia (40%), weight loss (32%), diarrhea (24%), skin rash (8%), leukopenia (8%), and genital ulcers (4%). We conclude that methyl-GAG has clear, albeit limited, activity against renal adenocarcinoma.

Both DFMO and methyl-GAG inhibit sequential enzymatic reactions in the pathway of polyamine biosynthesis. Since polyamines may be important factors in proliferation of cancer cells, we initiated a phase-I study of these agents in patients with advanced cancer. DFMO was given by mouth at a constant daily dose of 4 g/m2 starting on day 1 of the treatment protocol. The dose of methyl-GAG ranged from 200 to 700 mg/m2 administered IV every 2 weeks beginning on day 4. Twenty-two patients were entered into the protocol. Toxic reactions to this therapy were dose-related and included nausea, fatigue, diarrhea, and myelosuppression. One patient with colon cancer experienced a greater than 50% decrease in measurable disease but developed severe myelotoxicity. While DFMO was well tolerated, the combination of drugs appeared to cause substantially more hematologic and gastrointestinal toxicity than encountered during our recent experience with methyl-GAG used alone. We suggest that future studies of this drug combination carefully evaluate levels of polyamines and inhibition of enzymatic activity to minimize toxicity.

Methyl-GAG was given to 71 patients with advanced malignancies as a weekly brief infusion (30-120 minutes) or as a biweekly 24- or 120-hour infusion. Mucositis (stomatitis, pharyngitis, esophagitis, and, rarely, inflammation of other mucous membranes) was dose-limiting in all three schedules. Generalized fatigue, malaise, myalgia, dysesthesias, nausea, and vomiting were more frequent in the brief-infusion schedule. Myelosuppression was mild and not dose-related. Fever, ventricular arrhythmias, skin rash, tender swelling of the palms, neuropathy, and paralytic ileus were rare. Toxicity was increased in patients with renal insufficiency or "third-space" fluid but was not increased by hepatic dysfunction. Cumulative and overlapping toxicity was evident only in the weekly schedule. Higher doses of methyl-GAG were tolerated when the duration of infusion was increased. The recommended doses for phase II trials are 700 mg/m2 weekly as a 1-2 hour infusion, 850 mg/m2/24 hours biweekly, and 1500 mg/m2/120 hours biweekly. Therapeutic effects were seen in all schedules and included objective responses in colon carcinoma (one of 13 patients), renal cell carcinoma (one of nine), and Hodgkin's lymphoma (one of two) and objective improvements in esophageal carcinoma (one of three), endometrial carcinoma (two of two), and leiomyosarcoma (one of three).

Nineteen patients with locoregional non-small-cell lung cancer (NSCLC) were treated with two courses of cisplatin/VP-16/MGBG, followed by involved field radiotherapy and, subsequently, the same chemotherapy alternating with mitomycin-C/vinblastine. Five of 17 patients obtained a response (CR + PR) after induction chemotherapy. Following radiotherapy, an additional two patients responded. The median survival was 7.5 months, with the two longest survivors at 30 and 32 months. Hematologic toxicity was severe, with two deaths from severe neutropenia. Renal and gastrointestinal toxicities were moderate. This program of aggressive therapy did not increase the response rate or median survival compared with those of comparable patients treated in recent trials using radiotherapy alone or combined radiotherapy plus chemotherapy.

From 1981 to 1983, 208 patients with recurrent or refractory lymphoma were treated with methylglyoxal-bis-guanylhydrazone (methyl-GAG), ifosfamide, methotrexate, etoposide (MIME). The complete remission (CR) rate was 24% and CR plus partial remission (PR) was 60%. Response was higher for aggressive than for indolent cell types. Median duration of CRs was 16.5 months and median survival of all patients was 9 months. In view of the in vitro synergism between cisplatin and high-dose cytarabine, we recently designed the DHAP regimen, which consists of cisplatin, 100 mg/m2 IV over 24 hours; cytarabine, 2 g/m2 IV over two hours every 12 hours for two doses; and dexamethasone, 40 mg orally daily for 4 days. There were 28 of 90 (31%) CRs and 22 of 90 (24%) PRs. Median duration of CR is 15 months; median survival of all patients is 6 months. The major toxicities have been infection (31%) and moderate to severe renal dysfunction (20%). In contrast to MIME, response rates did not differ significantly between aggressive and indolent cell types. A high-dose regimen (CBV) consisting of cyclophosphamide, 6 g/m2; carmustine, 300 mg/m2; and etoposide, 250 mg/m2 daily for 3 days followed by autologous bone marrow transplant (ABMT) has been successfully used to treat 62 patients with Hodgkin's disease recurrent or refractory after mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (MOPP/ABVD)-like regimens. A CR rate (47%) has been observed; 83% of these CRs remain alive and free of disease with a median follow-up of 19 months. This regimen appears to have curative potential in 40% of all cases and in 60% of cases treated after the first or second relapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty-nine patients with metastatic breast cancer were treated with methyl-GAG at an initial starting dose of 500 mg/m2 iv weekly and then escalated by 50 mg/m2/week to tolerance. There were two partial responders among the 26 evaluable patients. Gastrointestinal and cutaneous reactions were the limiting toxic effects of methyl-GAG. Myelosuppression was mild and infrequent.

Methylglyoxal bis-dihydrochloride is a drug that has been available for use in cancer chemotherapy since 1955. In earlier studies, it was used on a daily schedule with resulting severe gastrointestinal toxicity and myelosuppression. To avoid that toxicity, a new weekly schedule has been adopted in several Phase II studies. With the weekly schedule, new types of toxicity have been described and we report four patients who have developed a severe sensory-motor neuropathy with the chemotherapy which appears to be drug-related.

Forty-four patients with advanced colon or rectal cancer were treated with methyl-GAG on a weekly schedule. Of the 40 evaluable patients, 35 (87%) had received prior chemotherapy. Objective tumor regression was seen in six patients (one CR, five PR's). An additional nine patients had stable disease for a median of 42 weeks. The median survival (42+ weeks) for responding and stable disease patients was significantly better (p = 0.0001 Wilcoxan test) than those with progressive disease (11 weeks). Toxicity was reversible and included mild to moderate mucositis, nausea, vomiting, diarrhea, and thrombocytopenia. Responses observed in this study warrant further trials in patients with colon cancer who have no prior chemotherapy.

A phase II study of Methylglyoxal-bis-guanylhydrazone (Methyl-GAG) was conducted on 20 previously treated patients with soft-tissue sarcomas. No major responses were seen among 18 adequately treated patients. Toxicity including severe fatigue, muscle pains, and pharyngitis was noted in most patients. Methyl-GAG does not have significant antitumor activity in previously treated patients with soft-tissue sarcomas.

Fifty-two patients with metastatic or recurrent non-small-cell lung cancer (NSCLC) were treated, during a phase II trial, with methylglyoxal-bis-(guanylhydrazone) (MGBG). Of the 44 patients who had adequate trials, 4 had partial responses (PR), for an overall 9% PR rate. Response durations ranged from 3 to 5+ months. Prior treatment with chemotherapy may have adversely affected response rate; 15% of previously untreated patients responded, compared to only 4% of previously treated patients. A syndrome of weakness and fatigue was the most serious side effect. Anorexia and weight loss, stomatitis, nausea and vomiting, diarrhea, and peripheral neuropathy were the other toxic effects. We conclude that MGBG has activity in NSCLC, especially in previously untreated patients, and further studies are indicated in that population.

The Southwest Oncology Group has evaluated methyl-GAG on a weekly schedule among patients with metastatic breast cancer. Among 72 fully and partial evaluable patients, one complete and four partial responses were seen. Toxicity was similar to other trials with this compound except for thrombocytopenia which was more frequent and severe and probably related to tumor infiltrating marrow. In addition, one patient experienced recall dermatitis following methyl-GAG. This toxicity has not been previously reported with this compound. Methyl-GAG has minimal activity at this dose and schedule among heavily pretreated patients with breast cancer.

Sixteen patients with primary malignant brain tumors, recurrent or progressive after surgery and radiation therapy, were treated with mitoguazone. Starting dose was 500 mg/m2 iv on a weekly schedule. In 15 evaluable patients no tumor regressions were observed. Four patients had stabilization of disease.

Thirty-nine patients received 600 mg/m2 OF MGBG intravenously every week for the treatment of advanced refractory ovarian cancer. Twenty-seven of these received adequate trials, and only two had partial remissions lasting 3 1/2 and 4 months each. Toxicity was substantial, with severe hematologic toxicity in 26%, diarrhea in 22% (severe in 7%), skin rash in 26% (severe in 7%), and vomiting in 70% (severe in 11%). Fatigue, facial paresthesias, and flushing during drug administration were frequent. It appears that MGBG in this dose and schedule has little activity against advanced ovarian cancer.

Transplantable prostate adenocarcinoma were treated with polyamine biosynthetic inhibitors. alpha-difluoromethylornithine (alpha-DFMO), an inhibitor of ornithine decarboxylase and by s-methylglyoxal-bisguanylhydrazone (MGBG), an inhibitor of s-adenosylmethionine decarboxylase. The therapeutic regimen of 0.8-1.11 g/kg DFMO reduced the tumor growth by 40% whilst the combination with 10.5 mg/kg MGBG completely destroyed the prostate adenocarcinomas in the tumor-bearing animals. The polyamine content of spermidine and spermine in the cancerous tissues is significantly lower whereas the putrescine levels remain unchanged. The MGBG therapy distinctly stimulates the activity of ornithine decarboxylase and increases the putrescine concentration up to toxic levels. The application of alpha-DFMO prevented the toxic accumulation of putrescine and allowed higher doses of MGBG. Clinical trials with polyamine antimetabolites appeared useful due to pathological polyamine excretion of patients with metastatic prostate cancer. The therapy with 0.2-0.3 g/kg DFMO in patients with hormone-resistent prostate cancer and metastasis displayed a moderate anti-tumor activity following 2 months additional treatment. High levels of side effects, however, were registered and were similar to those of other cytotoxic compounds. A combined therapy with DFMO/MGBG in a patient with metastatic anaplastic prostate cancer did not improve the survival rate but showed regressive effects of the histological pattern.

Thirty-six patients with adenocarcinoma or epidermoid carcinoma of the esophagus were entered into a phase II trial evaluating the combination of cisplatin 100 mg/m2 intravenously (IV) day 2, vinblastine 1.6 mg/m2 IV days 1 to 4, and mitoguazone (MGBG) 500 mg/m2 IV days 1 and 8. Twenty-nine patients (group A) were newly diagnosed with local-regional disease only and were candidates for transhiatal esophagectomy (THE). These patients received two courses of chemotherapy at 3-week intervals prior to surgery. Response was assessed by measuring changes in the primary tumor length and depth on serial biphasic contrast esophagrams and comparing this result with tumor measurements obtained from the surgical specimen. Complete (CR) and partial responders (PR) received three additional postoperative cycles. Seven patients had recurrent or metastatic disease (group B) and were treated every 4 weeks until disease progression. Of 34 patients evaluable for response, there was one pathologically confirmed CR and 15 PRs (47%). This consisted of 12 of 27 (44%) group A patients (seven of 11 epidermoid, five of 16 adenocarcinoma) and four of seven (57%) group B patients (two of four epidermoid, two of three adenocarcinoma). Toxicity included leukopenia in one third of treatment courses and thrombocytopenia in 21%. Nausea and vomiting occurred in 60% of patients, diarrhea in 18%, transient nephrotoxicity in 18%, peripheral neuropathy in 12%, and ototoxicity in 3%. Twenty-five group A patients underwent resection. Four chemotherapy nonresponders (NR) and one PR had known disease left at surgery; all others (80%) had gross total removal of their disease. The median survival time (MST) of the 29 group A patients was 14 months, with 21% alive at 36 months. The MST of group A chemotherapy responders was 15 months compared with 9 months for NRs (P = .032). Initial sites of recurrence in 14 patients were local-regional in six, distant only in six, both local-regional and distant in two. This regimen, administered in maximally tolerated doses, was active in epidermoid and adenocarcinoma histologies, recurrent disease and newly diagnosed patients. However, nearly all responses were PRs and the MST of resected patients was similar to a prior series of patients treated with esophagectomy alone. Observations from this pilot trial and those of others have led to a follow-up study, in progress, evaluating intensive preoperative chemotherapy and concurrent radiation therapy (RT).

This is a comparative study to evaluate response rate to mitoguazone (MGBG) and vinblastine (VLB) in 52 evaluable patients with advanced transitional cell carcinoma of the urinary tract. Of 38 patients with measurable disease, two of 18 (11%) on MGBG had partial remission (95% confidence interval: 0.01, 0.35), whereas four of 20 (20%) responded on the VLB arm (95% confidence level: 0.06-0.44). Both responses on the MGBG arm were seen in patients given prior chemotherapy. Side effects of both drugs were significant, with 46% of patients given VLB developing severe or life-threatening hematologic toxicity. Data indicate that both drugs, as single agents, are probably inferior to cisplatin for control of advanced transitional cell carcinoma of the urinary tract.

Thirty-four assessable patients with advanced squamous cell and adenocarcinoma of the lung were treated with weekly MGBG in a phase II trial. Only one partial response, in adenocarcinoma, was observed. Myelosuppression was mild to moderate. Major toxicities consisted of myalgia, myopathy, mucositis, gastrointestinal and pronounced vasculitis in one patient. It would appear that MGBG does not have sufficient antitumor activity to warrant further investigation in advanced squamous cell and adenocarcinoma of the lung.

We have tested methyl glyoxal bis-guanyl hydrazone (NSC 32946) for antitumor activity in patients with colorectal carcinoma and non-small cell bronchogenic carcinoma. The drug dose was 500 mg/m2 administered by single weekly injection, and with a provision dose escalation. No responses were seen in 38 evaluable patients with colorectal cancer, including 17 who had received no prior chemotherapy. Three responses were seen among 42 patients with bronchogenic carcinoma. These included one each with epidermoid carcinoma, adenocarcinoma and large cell anaplastic carcinoma. None of these responders had received prior chemotherapy. Toxicity of the drug was predominantly gastrointestinal, namely nausea, vomiting and diarrhea, and tended to increase with repeated drug doses. Neurologic symptoms of various sorts were also prominent. We conclude that methyl-G is of marginal benefit in this dose and schedule to patients with bronchogenic carcinoma.

Fourteen patients with metastatic renal cell carcinoma received methyl-G weekly at a starting dose of 600 mg/m2 (five patients) and 500 mg/m2 (nine patients) intravenously. All 14 patients are evaluable for response and toxicity. No antitumor responses were observed. Six patients achieved stabilization of disease for 8 to 42 weeks. Toxicity was nonhematologic and included nausea or vomiting (35%), fever with shaking chills (28%), diarrhea (21%), myalgia (63%), paresthesia (49%), and bilateral foot drop (7%). Methyl-G does not appear to have activity against renal cell carcinoma.