mitoguazone and Kidney-Neoplasms

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.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Eruptions; Drug Therapy, Combination; Eflornithine; Esophageal Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Leukemia; Leukemia L1210; Lung Neoplasms; Mice; Mitoguazone; Muscular Diseases; Nausea; Neoplasms; Ornithine; Polyamines; Stilbamidines; Structure-Activity Relationship

A trial of melphalan and methyl-gag was undertaken in 16 patients with metastatic renal cell carcinoma. Among 14 evaluable patients, 6 had stabilization of disease. No significant responses were observed. While both drugs have produced occasional responses in renal cancer, their combination shows no therapeutic advantage.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Melphalan; Middle Aged; Mitoguazone

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

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.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Eruptions; Drug Therapy, Combination; Eflornithine; Esophageal Neoplasms; Guanidines; Head and Neck Neoplasms; Humans; Kidney Neoplasms; Leukemia; Leukemia L1210; Lung Neoplasms; Mice; Mitoguazone; Muscular Diseases; Nausea; Neoplasms; Ornithine; Polyamines; Stilbamidines; Structure-Activity Relationship

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 polyamine metabolism is pathologically changed in tumor tissues, and especially putrescine and spermidine demonstrate abnormally high values in kidney, bladder, and prostate cancer. The inductive processes which activate the biosynthetic polyamine enzymes in cancer are completely unknown. Of therapeutic interest is the fact that increased enzyme activities through irreversible inhibitors become significantly reduced, which consequently slows the tumor growth. Experimental therapy, especially in transplantable bladder and prostate cancer, displayed a 50% tumor destruction. In clinical studies using inhibitors of the polyamine biosynthesis, the dose had to be significantly reduced because of expressed toxicity. Additional investigations which tried a combination of reversible and irreversible inhibitors proved a similar antitumor activity, but less severe side effects.

Topics: Adenosylmethionine Decarboxylase; Antimetabolites, Antineoplastic; Carboxy-Lyases; Drug Combinations; Eflornithine; Enzyme Induction; Enzyme Inhibitors; Humans; Kidney Neoplasms; Male; Mitoguazone; Ornithine; Polyamines; Prostatic Neoplasms; Urogenital Neoplasms

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

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

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

Topics: Drug Evaluation; Guanidines; Humans; Kidney Neoplasms; Middle Aged; Mitoguazone; Neuralgia; Vomiting

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

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