mitoguazone and Adenocarcinoma

Lung cancer treatment has been considered to have made little progress except for advances in small cell carcinoma. For other histologies an attitude of nihilism has prevailed principally because of lack of effective systemic therapy and of no persuasive evidence that results could be improved by combined modality treatment. On the other hand, favorable results from surgery are confined to a small percent of all patients with this disease. This review emphasizes possibilities for progress in evolving new therapeutic strategies. Although improvement over other systemic therapies is modest, cisplatin-containing regimens yield more consistent response rates and apparent survival advantage relative to single agents. Immediate progression occurs in the minority of patients. In addition, regimens combining cisplatin with vinca alkaloids have no substantial deleterious effects on the lung, marrow or esophagus to aggravate radiation-induced complications. These features encourage the evolution of strategies which begin with chemotherapy and then use consolidation with radiation therapy. Clinical trials using these and newer strategies must be instituted if progress is to occur in the treatment of non-small cell histologies at all stages.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Lung Neoplasms; Mitoguazone; Vinblastine; Vindesine

We designed a protocol to evaluate the possibility of organ preservation in patients with advanced, resectable carcinoma of the head and neck. The regimen consisted of intensive chemotherapy followed by radiation therapy alone for patients with good response to treatment. The end points of the study were response rate, organ preservation, toxicity, and survival.. Forty-two eligible patients with carcinoma of the oral cavity, oropharynx, hypopharynx, larynx, and paranasal sinuses were enrolled. Induction chemotherapy consisted of three cycles of mitoguazone, fluorouracil (5-FU), and high-dose continuous infusion cisplatin. Patients who had a complete response to chemotherapy, or whose tumor was downstaged to T1N1, were treated with definitive radiation therapy, to a total dose of 66 to 73.8 Gy. Patients with residual disease greater than T1N1 underwent surgery and postoperative radiation.. The overall response rate to chemotherapy was 84%, with a 43% complete response rate, and a 68% complete response rate at the primary tumor site. Sixty-nine percent of patients (29 of 42) were initially spared surgery to the primary tumor site, and four of these patients (14%) required neck dissection only, after radiation therapy. These tumor sites included oral cavity, oropharynx, hypopharynx, larynx, and sinuses. Eventually, five of these patients (17%) required salvage surgery and eight patients (28%) had unresectable or metastatic relapses. With a median follow-up duration of 38.5 months, 36% of all patients have had preservation of the primary tumor site and remain disease-free. The median survival duration is 26.8 months. Toxicity was substantial, with a 70% incidence of grade 3 to 4 granulocytopenia and two septic deaths.. Organ preservation without apparent compromise of survival was achieved in patients with selected nonlaryngeal sites of head and neck carcinoma. Larger site-specific trials with less toxic regimens conducted in randomized fashion are required to extend these data.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mitoguazone; Neoplasm Staging; Radiotherapy Dosage; Survival Analysis

Mitoguazone (methylglyoxal-bis(guanyl-hydrazone), MGBG) was studied by its first-pass mechanism in both cancer patients and experimental cancer models. It appears from the study that 90% of MGBG is cleared from the plasma within minutes. 24-h recovery in the urine, however, did not exceed 16% so that 84% of the drug seems to be bound to subcellular compartments. Tissue levels of MGBG in the normal prostate ranged higher than in experimental prostate cancer type 3327 M/G, i.e. enhanced clearance from cancer tissues: polyamine biosynthetic enzymes ornithine decarboxylase as well as S-adenosylmethionine decarboxylase are contrarily affected by MGBG.

Topics: Adenocarcinoma; Adenosylmethionine Decarboxylase; Animals; Carcinoma, Renal Cell; Cell Line; Cells, Cultured; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Infusions, Parenteral; Kidney Neoplasms; Male; Mice; Mice, Inbred Strains; Mitoguazone; Ornithine Decarboxylase; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Tissue Distribution

Lung cancer treatment has been considered to have made little progress except for advances in small cell carcinoma. For other histologies an attitude of nihilism has prevailed principally because of lack of effective systemic therapy and of no persuasive evidence that results could be improved by combined modality treatment. On the other hand, favorable results from surgery are confined to a small percent of all patients with this disease. This review emphasizes possibilities for progress in evolving new therapeutic strategies. Although improvement over other systemic therapies is modest, cisplatin-containing regimens yield more consistent response rates and apparent survival advantage relative to single agents. Immediate progression occurs in the minority of patients. In addition, regimens combining cisplatin with vinca alkaloids have no substantial deleterious effects on the lung, marrow or esophagus to aggravate radiation-induced complications. These features encourage the evolution of strategies which begin with chemotherapy and then use consolidation with radiation therapy. Clinical trials using these and newer strategies must be instituted if progress is to occur in the treatment of non-small cell histologies at all stages.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Lung Neoplasms; Mitoguazone; Vinblastine; Vindesine

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.

Topics: Adenocarcinoma; Adult; Aged; Alopecia; Clinical Trials as Topic; Drug Evaluation; Esophageal Neoplasms; Female; Guanidines; Head and Neck Neoplasms; Humans; Kidney; Lung Neoplasms; Lymphoma; Male; Middle Aged; Mitoguazone; Skin Diseases; Ulcer

A series of novel aromatic derivatives based on the structure of methylglyoxal bis(guanylhydrazone) (MGBG) was examined for in vitro antitrypanosomal activities and cytotoxicities for human cells. One-third of the compounds tested showed trypanocidal activity at concentrations below 0.5 microM after an incubation period of 72 h. Structure-activity analysis revealed that bicyclic compounds with homocyclic rings and unmodified termini were the most active compounds. Results obtained in three laboratories employing different methods and trypanosome populations consistently ranked compound CGP 40215A highest. This compound had a 50% inhibitory concentration of 0.0045 microM for Trypanosoma brucei rhodesiense, was also active against other trypanosome species, including a multidrug-resistant Trypanosoma brucei brucei, and was significantly less toxic than other compounds tested for a human adenocarcinoma cell line, with a 50% inhibitory concentration of 1.14 mM. The effect of CGP 40215A was time and dose dependent, and low concentrations of the compound required exposure times of > 2 days to exert trypanocidal activity. Compounds were inactive against Leishmania donovani and Trypanosoma cruzi amastigotes in murine macrophages in vitro.

Topics: Adenocarcinoma; Adenosylmethionine Decarboxylase; Animals; Humans; Mitoguazone; Structure-Activity Relationship; Time Factors; Trypanocidal Agents; Trypanosoma; Tumor Cells, Cultured

Topics: Adenocarcinoma; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mitoguazone; Neoplasm Recurrence, Local

The Eastern Cooperative Oncology Group (ECOG) entered 326 patients with advanced measurable colorectal cancer into four phase II drug or drug combination trials. Previously treated and chemotherapy-naive patients were eligible. Chlorozotocin was administered to 83 patients (51 previously treated), methyl-glyoxal-bis-guanylhydrozone (MGBG) to 90 patients (58 previously treated), and two regimens of the three-drug combination of cyclophosphamide, vincristine, and methotrexate (COM) to 153 patients (120 previously treated). The multidrug regimen had been developed specifically for previously treated patients. In this trial, chemotherapy-naive patients were no more likely to respond than were members of the previously-treated group. Even among previously untreated patients, response rates did not exceed 10% in any of these phase II programs. They are not recommended for further trials in patients with colorectal cancers.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Cyclophosphamide; Drug Evaluation; Humans; Methotrexate; Mitoguazone; Rectal Neoplasms; Streptozocin; Vincristine

Mice and rats of various ages (3, 10-12, and 18-19 months) were inoculated with the transplantation tumours murine melanoma B16 (B16), mammary adenocarcinoma 755 (Ca-755), leukemia P388 (P388), and rat rhabdomyosarcoma RA-2 (RA-2). Subcutaneous (sc) growth of B16 was not markedly affected by the age of the syngeneic host whereas intravenously (iv) inoculated 12 months old C57BL/6 mice developed more pulmonary metastases than animals 3 months of age. Median survival time (MST) of 18 months old mice bearing Ca-755 was significantly shorter than that of younger individuals. In contrast, old rats that had been injected RA-2 iv survived longer than controls. Survival of DBA/2 mice inoculated intraperitoneally (ip) with P388 cells was not influenced by the age of the host. The antineoplastic activity of ambazone and, to a less extent, of 5-fluorouracil against P388 was drastically lower in 12 months old mice than in 3 months old tumour bearers. Likewise a graduate loss of antineoplastic activity of ambazone against Ca-755 was observed with increasing age of the mice, whereas the effect of ambazone and 5-fluorouracil against RA-2 did not depend on the age of the rats. It is suggested that tumour-host interactions as well as pharmacokinetics of a given drug may underlie age-related changes.

Topics: Adenocarcinoma; Aging; Animals; Antineoplastic Agents; Cell Division; Female; Fluorouracil; Leukemia P388; Leukemia, Experimental; Male; Mammary Neoplasms, Experimental; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mitoguazone; Neoplasm Metastasis; Rats; Rhabdomyosarcoma

The mitochondria of carcinoma cells retain the permeant cationic compound rhodamine 123 longer than the mitochondria of normal epithelial cells. The possibility of exploiting this difference in the chemotherapy of a murine renal adenocarcinoma was investigated. Rhodamine 123 exhibited anticarcinoma activity in mice and this activity was potentiated by 2-deoxyglucose and methylglyoxal bis(guanylhydrazone), a chemotherapeutic agent that is toxic to mitochondria. Prolonged retention of rhodamine 123 by renal tumor cells compared with normal renal epithelial cells was demonstrated by flow cytometry, perhaps explaining its antitumor activity. A combination of both mitochondrial toxins, rhodamine 123 and methylglyoxal bis(guanylhydrazone) produced the longest survival and had the greatest antitumor effect.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Deoxyglucose; Kidney Neoplasms; Male; Mice; Mice, Inbred BALB C; Mitochondria; Mitoguazone; Rhodamine 123; Rhodamines; Xanthenes

The effects of two inhibitors of ornithine decarboxylase activity, alpha-difluoromethylornithine (DMFO) and (2R,5R) 6-heptyne-2,5 diamine (HDA), and an inhibitor of S-adenosylmethionine decarboxylase, methylglyoxal bis-guanylhydrazone (MGBG), were tested on casein kinase activity and endogenous phosphorylation in the cytosol fractions of mouse thyroid and a rat prostate tumor model, Dunning R 3327 MAT LyLu subline. When tested at 5 mM, spermine, DMFO, HDA, and MGBG stimulated mouse thyroid casein kinase activity by 230%, 14%, 65% and 106%, respectively. Similar responses were observed in prostate tumor cytosol. In mouse thyroid cytosol, spermine stimulates 32P incorporation primarily into 3 proteins (MW: 107, 88, and 56 kDa). At 5 mM, MGBG partially reproduces the effects of spermine; HDA is less effective and DMFO is without effect. Similar effects were observed on 3 proteins in prostate tumor cytosol with molecular weights of 91, 41, and 32 kDa. These data provide additional support for the hypothesis that the observed synergistic inhibitory effect of DMFO and MGBG on cell growth may not be due solely to the inhibition of polyamine biosynthesis. Our findings suggest that MGBG-mediated reduction in the phosphorylation of casein kinase substrate should be considered as one locus of action.

Topics: Adenocarcinoma; Adenosylmethionine Decarboxylase; Alkynes; Animals; Antineoplastic Agents; Casein Kinases; Cytosol; Diamines; Eflornithine; Female; Male; Mice; Mitoguazone; Ornithine Decarboxylase Inhibitors; Phosphoproteins; Phosphorylation; Prostatic Neoplasms; Protein Kinases; Rats; Spermine; Thyroid Gland

The antitumor effects of two polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG), when combined with cis-diamminedichlroplatinum (CDDP) or mitomycin C (MMC), were studied using human gastric cancer cells xenotransplanted into nude mice. DFMO 1000 mg/kg and MGBG 50 mg/kg were given intraperitoneally for 6 successive days, while CDDP 3 mg/kg or MMC 2 mg/kg was given every second day. Although DFMO and MGBG plus MMC did suppress the tumor growth, the combination with CDDP led to no suppression, and rapid growth occurred after the cessation of therapy. The inhibition of tumoral DNA biosynthesis and a decline in polyamine levels, were also not observed. The polyamine antimetabolites when used with CDDP did not produce the desired antitumor efficacy, even though the platinum concentration in the tumor tissue was high. On the contrary, however, DFMO and MGBG when combined with MMC did suppress tumor growth, inhibited DNA biosynthesis, and tissue polyamine levels were low. These results suggest that though CDDP and MMC belong to a similar category of DNA attacking, bifunctional alkylating agents, the findings of these two drugs are contradictory. Here, the mechanism of action no doubt plays a contributory role.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; DNA; Drug Interactions; Eflornithine; Female; Humans; Mice; Mice, Inbred BALB C; Mitoguazone; Mitomycins; Neoplasm Transplantation; Polyamines; Stomach Neoplasms; Transplantation, Heterologous

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).

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Evaluation; Esophageal Neoplasms; Humans; Mitoguazone; Vinblastine

Both alpha-difluoromethyl ornithine (DFMO) and methylglyoxal bis (guanylhydrazone) (MGBG) inhibit sequential enzymatic reactions in the pathway of polyamine biosynthesis. Since polyamines may be important factors in proliferation of cancer cells and DFMO combined with MGBG has shown synergistic cytotoxicity in an experimental prostatic tumor, we evaluated these agents in phase I clinical trial involving 5 patients with advanced, hormone-resistant prostatic cancer. Toxic reaction to combined DFMO and MGBG was dose-related and included nausea, fatigue, and diarrhea especially with the higher doses of MGBG. No therapeutic responses of significance were seen, but toxicity precluded adequate evaluation. Future Phase II studies of combined DFMO and MGBG should employ low, nontoxic doses of MGBG combined with evaluation of polyamine levels and inhibition of polyamine enzymatic activity to minimize toxicity.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Evaluation; Eflornithine; Humans; Male; Mitoguazone; Prostatic Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Mitoguazone; Pancreatic Neoplasms; Stomach Neoplasms

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.

Topics: Adenocarcinoma; Adenosylmethionine Decarboxylase; Animals; Antineoplastic Agents; Carboxy-Lyases; Carcinoma; Eflornithine; Estrogens; Humans; Male; Mitoguazone; Neoplasm Metastasis; Ornithine; Ornithine Decarboxylase Inhibitors; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatitis; Putrescine; Rats; Spermidine; Spermine

The effect of cisplatin, carboplatin, and mitoguazone dihydrochloride on pancreatic cancer was evaluated using pancreatic ductal adenocarcinomas Capan-1, Capan-2, and PR54 grown in the nude mouse. In single agent treatments, cisplatin, given in the amount of 5 mg/kg once/week for 4 consecutive weeks, was most effective, resulting in tumor regression, growth arrest, and a growth delay period of 6 and 4 months for tumors Capan-1 and PR54, respectively. Treatment with carboplatin was less effective, with a tumor response related to treatment schedule. For the same amount of total dose of carboplatin administered, best results were obtained when treatment was given 3 times weekly instead of in single weekly injections. Mitoguazone dihydrochloride exhibited no antitumor effect. The results of the present work may be of significance in the management of pancreatic cancer patients.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carboplatin; Cisplatin; Female; Guanidines; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mitoguazone; Neoplasm Transplantation; Organoplatinum Compounds; Pancreatic Neoplasms; Transplantation, Heterologous

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.

Topics: Adenocarcinoma; Aged; Drug Evaluation; Guanidines; Humans; Male; Middle Aged; Mitoguazone; Neoplasm Metastasis; Prostatic Neoplasms; Tomography, X-Ray Computed

Two hundred six different samples of human renal carcinoma were tested for in vitro chemotherapy sensitivity using a soft agar colony formation assay similar to that originally described by Salmon and colleagues. Eighty of 159 (50 per cent) evaluable tumor tests showed colony formation in vitro and gave clinical drug sensitivity information. Two-thirds of tumors were resistant to all drugs tested, despite a median number of drugs tested per tumor of 14.5. Five tumors (6 per cent) were remarkably sensitive to numerous anticancer drugs in vitro. The most active drugs found in vitro were teniposide, actinomycin D, bleomycin, hydroxyurea, mitoguanazone dihydrochloride, mitomycin C and L-alanosine. Fourteen other drugs tested showed low in vitro cytotoxicity.

Topics: Adenocarcinoma; Agar; Antineoplastic Agents; Bleomycin; Cells, Cultured; Dactinomycin; Drug Evaluation; Humans; Hydroxyurea; Kidney Neoplasms; Mitoguazone; Nephrectomy; Teniposide

The polyamines, putrescine, spermidine, and spermine, are fundamentally related to both normal and neoplastic cell proliferation. The prostate gland and prostatic tumors in man and rodents contain large amounts of polyamines. This suggests that inhibition of polyamine biosynthetic enzymes, ornithine decarboxylase (ODC) and S-adenosyl-methionine decarboxylase (SAMDC) may retard the growth of prostatic cancer. Since alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG) are irreversible and competitive inhibitors of ODC and SAMDC, respectively, they were tested as single agents and in combination on a transplantable rapidly growing and hormone-resistant G subline of the Dunning R-3327 rat prostatic adenocarcinoma. Groups of rats bearing tumors were treated with various regimens of DFMO, MGBG, and DFMO plus MGBG, daily for 21 days. Analysis of differences in tumor growth between treatment groups and controls showed DFMO had no antitumor effect but was well tolerated, MGBG retarded growth rate significantly but resulted in drug deaths in over 50% of the animals, and the combination of DFMO and MGBG resulted in rapid decline in tumor growth rates after 5 to 9 days of treatment with reduced toxicity. At 21 days, or death, 38 of 60 (63%) rats had no viable tumor on histologic study, whereas tumor was present in each of the animals in the other groups. Alpha-difluoromethylornithine increased the intracellular uptake of MGBG and potentiated the antigrowth activity of MGBG on a hormone refractory rat prostatic tumor with less toxicity than MGBG alone.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Line; Drug Synergism; Eflornithine; Guanidines; Humans; Male; Mitoguazone; Neoplasm Transplantation; Ornithine; Prostatic Neoplasms; Rats; Rats, Inbred Strains

Difluoromethylornithine (DFMO) and methylglyoxal-bis(guanyl-hydrazone) (MGBG), inhibitors of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AMDC), respectively, were tested in two experimental prostatic cancer models. DFMO resulted in a reduction in tumor size in both the rapidly growing R-3327 rat prostatic adenocarcinoma (30.5 +/- 15 versus 61 +/- 9.5 in control animals) and the human DU-145 adenocarcinomas (1.7 ml versus 3.3 ml in control animals) in nude mice. MGBG was tested only in the rat tumor, where it induced a reduction of 22.9 +/- 9.5 ml versus 61 +/- 9.5 in control animals in tumor size but was highly toxic. Flutamide or 9-B-D-arabinofuranosyladenine (Ara-A) proved ineffective per se in reducing tumor growth of the human DU-145 or of the R-3327-G strain, respectively, but increased the efficacy of DFMO against the DU-145 tumor had a high level of ODC which was reduced by DFMO of by Ara-A; the R-3327 tumor had a low level of ODC which was too low to be decreased by DFMO.

Topics: Adenine; Adenocarcinoma; Adenosylmethionine Decarboxylase; Animals; Carboxy-Lyases; Eflornithine; Guanidines; Male; Mice; Mice, Nude; Mitoguazone; Ornithine; Ornithine Decarboxylase Inhibitors; Polyamines; Prostatic Neoplasms; Rats; Vidarabine

alpha-Difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG), when administered simultaneously, inhibited growth and were highly toxic to the Dunning R 3327-G hormone-resistant prostatic adenocarcinoma transplanted into Copenhagen rats. Neither DFMO (2%) nor MGBG at a nontoxic dose (15 mg/kg) inhibited tumor growth, but total (47% early cure rate) or near total suppression of growth of established tumors was observed in rats receiving both treatments.

Topics: Adenocarcinoma; Animals; Body Weight; Cell Division; Drug Therapy, Combination; Eflornithine; Guanidines; Male; Mitoguazone; Ornithine; Polyamines; Prostatic Neoplasms; Rats; Rats, Inbred Strains

alpha-Difluoromethylornithine (DFMO) and methylglyoxal bis-(guanylhydrazone) (MGBG) were tested against a murine renal adenocarcinoma, because polyamines are necessary for neoplastic cell growth and because human renal adenocarcinomas contain higher levels of spermidine than do normal renal cells; MGBG inhibits spermidine synthesis and has some activity against human renal tumors; DFMO irreversibly inhibits ornithine decarboxylase, the first rate-limiting enzyme controlling polyamine biosynthesis; and DFMO promotes intracellular accumulation of MGBG in experimental tumor models and human leukemia. DFMO (2%) in drinking water, MGBG (15 mg/kg i.p.), or a combination of DFMO and MGBG was administered daily to BALB/c mice (n = 80) with intrarenal transplants of renal adenocarcinoma cells. At 28 days, renal carcinomas weighed 64 and 73% less, respectively, in DFMO- and DFMO-MGBG-treated mice than in control animals (p less than 0.01). MGBG alone had no antigrowth effect. DFMO-MGBG reduced the total metastatic index (total number of metastases/total number of animals) to 1.2 versus 3.6 in control animals (p less than 0.01) and increased survival by 12.3 +/- 1.5 (S.E.) days, from 30.8 to 42.5 days (p less than 0.05). Compared with control, DFMO-, or MGBG-treated animals, DFMO-MGBG exposure reduced tumor growth and the number of metastases, prevented metastases in some animals (47%), and increased survival of mice bearing renal adenocarcinomas. DFMO also appeared to selectively increase the uptake of [14C]MGBG by tumor tissue, which may help to explain the enhanced synergistic antigrowth effect of DFMO and MGBG against this murine renal adenocarcinoma.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Body Weight; Cell Division; Drug Synergism; Eflornithine; Guanidines; Kidney Neoplasms; Male; Mice; Mice, Inbred BALB C; Mitoguazone; Neoplasm Metastasis; Ornithine; Tissue Distribution

Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Guanidines; Head and Neck Neoplasms; Humans; Middle Aged; Mitoguazone

Difluoromethylornithine (DFMO) and methylglyoxal bis (guanylhydrazone) (MGBG), inhibitors of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AMDC), respectively, were tested for antitumor activity in the BALB/C mouse renal adenocarcinoma model, wherein ODC and AMDC activity are elevated compared to the normal kidney. Additionally, an indirect effector of AMDC synthesis, arabinofuranosyladenine and an inhibitor of AMDC synthesis, cycloleucin (CL), were tested in this model. Simultaneous administration of both DFMO and MGBG affected the growth of renal adenocarcinoma less than did administration of DFMO or MGBG alone. Combinations of inhibitors of polyamine synthesis demonstrated a high toxicity with low therapeutic activity. The most effective tumor suppression was observed with CL alone but associated toxicity was severe. Suramin, an ODC stimulator, may have enhanced tumor growth.

Topics: Adenocarcinoma; Animals; Eflornithine; Guanidines; Kidney; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Mitoguazone; Neoplasms, Experimental; Ornithine; Polyamines

Methyl-GAG at low doses was administered to an anephric male patient with metastatic hypernephroma, who required hemodialysis. No toxicity was observed. Measurement of serum levels of methyl-GAG showed that the drug is dialyzable. Thus, when methyl-GAG is considered for patients who are anephric and are being dialyzed, full doses are allowable. In addition, dialysis should be effective in rapidly eliminating the drug in patients who develop toxic effects.

Topics: Adenocarcinoma; Guanidines; Humans; Infusions, Parenteral; Kidney Neoplasms; Male; Middle Aged; Mitoguazone; Renal Dialysis

The effect of Methyl-GAG on a transplantable murine renal cell adenocarcinoma was evaluated. Inoculation of Balb/C mice with 1 X 10(5) renal adenocarcinoma cells under the renal capsule resulted in 100% tumor growth and death of the animal in 29 +/- 5 days. In 66% of the control animals lung metastases was observed. Intraperitoneal injections of Methyl-GAG at dose levels of 200 mg/m2, 150 mg/m2, and 100 mg/m2 administered weekly failed to demonstrate any effect on local growth of the tumor. More than 50% incidence of metastatic development was noted in the treated groups. Methyl-GAG had no apparent effect on primary tumor growth or the retardation of metastatic incidence.

Topics: Adenocarcinoma; Animals; Body Weight; Guanidines; Kidney Neoplasms; Male; Mice; Mice, Inbred BALB C; Mitoguazone; Neoplasm Transplantation; Neoplasms, Experimental

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Drug Evaluation; Drug Therapy, Combination; Female; Guanidines; Humans; Kidney Neoplasms; Male; Middle Aged; Mitoguazone; Vinblastine

Topics: Adenocarcinoma; Guanidines; Humans; Kidney Neoplasms; Mitoguazone

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.

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Evaluation; Female; Guanidines; Humans; Infusions, Parenteral; Lung Neoplasms; Male; Middle Aged; Mitoguazone

In a phase II study of methyl-glyoxal bis-guanylhydrazone (methyl-GAG) in patients with bi-dimensionally measurable metastases of renal cell cancer, 30 patients were given 500 mg/m2 weekly for at least 4 treatment cycles and were evaluable for response. Three patients (10%) achieved partial remission (PR) with a duration of 8-12 weeks; in 11 patients the disease was assessed as stable; and in 16 there was progression. A total of 40 patients were evaluable for toxicity. Nausea and vomiting occurred in 17 (43%), neuropathy, myopathy or myalgia in 8 (21%) and mucositis in 6 (14%). In addition to 3 patients taken off treatment before 4 treatment cycles, toxicity precluded further treatment in 3 others after 5, 6 and 7 cycles respectively. Methyl-GAG has minimal activity in renal cell cancer and, in this dose schedule, causes appreciable toxicity.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Digestive System; Drug Evaluation; Guanidines; Humans; Kidney Neoplasms; Middle Aged; Mitoguazone; Nervous System

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.

Topics: Adenocarcinoma; Anorexia; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Drug Evaluation; Fatigue; Female; Guanidines; Humans; Lung Neoplasms; Male; Mitoguazone

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.

Topics: Adenocarcinoma; Adult; Aged; Dose-Response Relationship, Drug; Drug Evaluation; Drug Resistance; Female; Guanidines; Humans; Male; Middle Aged; Mitoguazone; Nausea; Neoplasm Metastasis; Neoplasms; Paresthesia; Vomiting

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Chemistry, Pharmaceutical; Guanidines; Hydrazines; Leukemia L1210; Leukemia, Experimental; Mitoguazone; Neoplasms; Neoplasms, Experimental; Pharmacology; Pyruvaldehyde; Research; Sarcoma 180