germanium and spirogermanium

Topics: Animals; Germanium; Humans; Organometallic Compounds; Radioisotopes; Spiro Compounds

One hundred forty-four patients with non-small cell lung cancer, the majority (72%) of whom had received previous chemotherapy, were evaluable in this randomized phase II study of N-methylformamide (N-MF), spirogermanium, and 4-demethoxydaunorubicin. There were two partial responses, one each with spirogermanium and 4-demethoxydaunorubicin. There were eight life-threatening complications (mostly hematologic) and two lethal complications (N-MF, hematologic; 4-demethoxydaunorubicin, gastrointestinal). The overall survival ranged from 9 days to 533 days with a median of 17.6 weeks. The following factors were associated with poor survival: Poor initial performance status, prior weight loss, presence of liver or subcutaneous metastases.

Topics: Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Female; Formamides; Germanium; Humans; Idarubicin; Lung Neoplasms; Male; Middle Aged; Organometallic Compounds; Prognosis; Random Allocation; Remission Induction; Spiro Compounds

Germanium is present in all living plant and animal matter in micro-trace quantities. Its therapeutic attributes include immuno-enhancement, oxygen enrichment, free radical scavenging, analgesia and heavy metal detoxification. Toxicological studies document Germanium's rapid absorption and elimination from the body, and its safety. Clinical trials and use in private practices for more than a decade have demonstrated Germanium's efficacy in treating a wide range of serious afflictions, including cancer, arthritis and senile osteoporosis. Germanium's anti-viral and immunological properties, including the induction of interferon, macrophages, T-suppressor cells and augmentation of natural killer cell activity, suggest its possible efficacy in treating and/or preventing AIDS.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antineoplastic Agents; Arthritis; Clinical Trials as Topic; Female; Germanium; Humans; Leukemia, Experimental; Lung Neoplasms; Lymphoproliferative Disorders; Malaria; Organometallic Compounds; Osteoporosis; Ovarian Neoplasms; Spiro Compounds

Spirogermanium, a heavy metal compound in which germanium has been substituted in an azaspirane ring structure, was studied in 39 patients with advanced malignant neoplasms. Thirty-one patients were considered evaluable for toxic effects of spirogermanium. Transient neurological symptoms occurred in 12 patients (39%), including dizziness or lightheadedness, marked fatigue, visual blurring, ataxia, paresthesia, and nausea. These symptoms could be reduced by infusing the drug over 2 hours rather than over 1 hour. Persistent neurotoxicity in the form of partial loss of taste or extreme weakness was observed in three patients. No evidence of hematologic, renal, or hepatic toxicity was observed. Antitumor activity of spirogermanium was not identified in this group of heavily pretreated patients. Spirogermanium had limited and acceptable toxicity in utilizing a dose of 120 mg/m2 infused over 2 hours, three times weekly.

Topics: Adult; Aged; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Female; Germanium; Half-Life; Humans; Infusions, Parenteral; Kinetics; Male; Middle Aged; Neoplasms; Organometallic Compounds; Spiro Compounds

Topics: Adult; Aged; Cerebral Hemorrhage; Chemical and Drug Induced Liver Injury; Drug Evaluation; Female; Germanium; Glioma; Humans; Male; Middle Aged; Nervous System Neoplasms; Organometallic Compounds; Spiro Compounds

Topics: Adult; Aged; Carcinoma, Renal Cell; Drug Evaluation; Female; Germanium; Humans; Kidney Neoplasms; Male; Middle Aged; Organometallic Compounds; Spiro Compounds

Five drugs, selected because of minimal in vivo myelotoxicity, have been investigated for inhibition of the growth of three acute lymphatic leukemia-derived cell lines. Granulocyte-macrophage colony-forming units (GM-CFU) inhibition with these five drugs after 60-min incubation was first established. Drug concentrations giving up to 90% kill of GM-CFU were then used. Spirogermanium and L-asparaginase did not have an effect on any of the three cell lines under the culture conditions tested, while 4-hydroperoxycyclophosphamide (4-HC) and vincristine inhibited the growth of all three cell lines tested, and bleomycin inhibited the growth of two cell lines. In addition to 4-HC, bleomycin and vincristine should be considered as possible agents in eliminating leukemic cells from autologous marrow grafts. These drugs also deserve further investigation in clonal systems.

Topics: Antineoplastic Agents; Asparaginase; Bleomycin; Bone Marrow; Bone Marrow Cells; Cell Division; Cell Line; Cyclophosphamide; Germanium; Hematopoietic Stem Cells; Humans; Kinetics; Leukemia, Lymphoid; Organometallic Compounds; Spiro Compounds; Vincristine

Spirogermanium is a novel metal containing azaspirane compound with reported antitumor activity. The results of the present investigation demonstrate that spirogermanium also exhibits antiarthritic and immunoregulatory activities after p.o. administration to rats. Spirogermanium decreased hindleg inflammatory lesions of adjuvant arthritic rats when administered p.o. before or after the development of the arthritic lesions. After termination of spirogermanium administration, the adjuvant-injected hindleg lesions remained significantly suppressed for at least 2 weeks postdrug treatment; whereas, the uninjected, immune-mediated hindleg inflammation tended to increase postdrug treatment. In multiparameter ex vivo studies, untreated arthritic rats exhibited enhanced cyanine dye fluorescence in peripheral blood monocytes, enhanced interleukin (IL)-1 production by adherent spleen cells and depressed IL-2 and IL-3 production by splenic lymphocytes. Spirogermanium normalized these changes to various degrees, with the exception of the depressed IL-2 and IL-3 production. Spirogermanium administered to normal nonarthritic rats decreased mitogenic responses of spleen cells to Concanavalin A which was found to be caused, at least in part, by enhanced suppressor cell activity. The antiarthritic and immunoregulatory profile of spirogermanium appeared to be different from the profiles of the antiarthritic agents, auranofin and indomethacin.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Arthritis; Arthritis, Experimental; Auranofin; Aurothioglucose; Concanavalin A; Fluorescence; Germanium; Immunosuppressive Agents; Indomethacin; Interleukin-1; Interleukin-2; Macrophages; Male; Monocytes; Organometallic Compounds; Rats; Rats, Inbred Lew; Spiro Compounds; T-Lymphocytes, Regulatory

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Evaluation; Female; Germanium; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Organometallic Compounds; Spiro Compounds

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Germanium; Humans; Lymphoma; Middle Aged; Organometallic Compounds; Seizures; Spiro Compounds

Topics: Aged; Antineoplastic Agents; Drug Evaluation; Germanium; Humans; Male; Middle Aged; Neoplasm Metastasis; Organometallic Compounds; Prostatic Neoplasms; Spiro Compounds

A phase II study of spirogermanium was conducted in a series of 15 patients with metastatic prostatic carcinoma. All the patients have previously received multiple hormonal therapies. The drug was administered at the dose of 200 mg/m2 by a continuous infusion for five days, and 120 mg/m2, three times a week subsequently. The side effects were mainly neurological toxicity and phlebitis at the injection points which were dose and schedule dependent. Only one partial response for two months was noted in this series. Thus, spirogermanium seems to have a limited value in patients with prostatic cancer.

Topics: Aged; Antineoplastic Agents; Drug Evaluation; Germanium; Humans; Male; Middle Aged; Neoplasm Metastasis; Organometallic Compounds; Prostatic Neoplasms; Spiro Compounds

Daily oral administration of spirogermanium to Lewis rats resulted in the generation of radiation-resistant (2000 Rad) suppressor cells which inhibited the proliferative response of normal spleen cells to an optimum concentration of concanavalin A. These suppressor cells became evident after three to six days of spirogermanium administration. After one day's treatment, although no suppressor cells could be detected, the response of these cells to concanavalin A was less than 50% of controls. Experiments designed to characterize the cell type(s) responsible for this suppression resulted in the finding that T cell-'depleted' populations of spleen cells were more suppressive than T cell-'enriched' populations. The induction of suppressor cells by spirogermanium and the previously described activity in the adjuvant arthritic rat model suggest therapeutic potential for autoimmune diseases.

Topics: Animals; Antineoplastic Agents; Cells, Cultured; Concanavalin A; Germanium; Kinetics; Lymphocyte Depletion; Male; Organometallic Compounds; Rats; Rats, Inbred Lew; Spiro Compounds; Spleen; T-Lymphocytes, Regulatory

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Germanium; Humans; Infusions, Parenteral; Middle Aged; Organometallic Compounds; Ovarian Neoplasms; Spiro Compounds

Topics: Adult; Carcinoma, Squamous Cell; Drug Evaluation; Female; Germanium; Humans; Infusions, Parenteral; Middle Aged; Organometallic Compounds; Prognosis; Spiro Compounds; Uterine Cervical Neoplasms

The National Cancer Institute of Canada Clinical Trials Group conducted a phase II study of spirogermanium given daily for 5 days every 3 weeks to previously untreated patients with malignant melanoma. In 21 evaluable patients one complete response was seen (response rate 5%). Disease progression occurred in the other 20 patients. Toxicity was primarily neurologic and mild or moderate in most patients, though there was one treatment related death. In this schedule spirogermanium has extremely limited activity against malignant melanoma and will not contribute significantly to the systemic therapy of this disease.

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Germanium; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Organometallic Compounds; Spiro Compounds

The National Cancer Institute of Canada Clinical Trials Group conducted a phase II study of spirogermanium given daily for 5 days every 3 weeks to patients with poor prognosis non-Hodgkin's lymphomas. All patients had had a maximum of one prior treatment regimen. No responses were seen in 13 evaluable patients. Toxicity was primarily neurologic and mild or moderate in most patients. There is no evidence of activity of spirogermanium given in this schedule in this subset of lymphoma patients.

Topics: Aged; Antineoplastic Agents; Drug Evaluation; Germanium; Humans; Lymphoma; Middle Aged; Nervous System Diseases; Organometallic Compounds; Prognosis; Spiro Compounds

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Central Nervous System Diseases; Drug Evaluation; Female; Germanium; Humans; Infusions, Parenteral; Middle Aged; Organometallic Compounds; Spiro Compounds

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation; Female; Germanium; Humans; Middle Aged; Neoplasm Metastasis; Organometallic Compounds; Receptors, Estrogen; Spiro Compounds

We have evaluated the toxicity of the antitumor agent spirogermanium on a schedule of continuous intravenous administration for periods up to five days. The doses tested were between 100 mg/m2/day and 500 mg/m2/day. Peripheral vein phlebitis occurred at all dose levels and was not relieved by addition of hydrocortisone or heparin to the infusion. No phlebitis occurred when the drug was administered through a central vein. The dose limiting toxicity of spirogermanium was neurologic, notably tremors and mental confusion. These problems became progressively more severe at doses above 250 mg/m2/day. There was no discernible bone marrow, renal or hepatic toxicity. One patient developed reversible interstitial pneumonitis. The recommended Phase II dose of spirogermanium is 200 mg/m2/day for five days, with the possibility of escalation in selected patients. Because spirogermanium is more toxic to tumor cells with prolonged exposure than with intermittent exposure, this schedule could be considered for Phase II trials, particularly in diseases thought to be especially sensitive such as ovarian and prostatic carcinoma or lymphomas.

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Germanium; Humans; Infusions, Parenteral; Male; Middle Aged; Neoplasms; Nervous System; Organometallic Compounds; Phlebitis; Spiro Compounds

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Germanium; Humans; Kidney Neoplasms; Male; Middle Aged; Organometallic Compounds; Spiro Compounds

A series of continuous human tumour cell lines, derived from various tumour types, were used to establish whether the combination of spirogermanium (SP) with other 'standard' antitumour drugs proved superior to these as single agents in reducing cell survival in vitro. A non-cytotoxic concentration of SP was selected and when combined with a range of concentrations of cisplatin or 5-fluorouracil (5-FU), definite synergistic cell kill was noted in all lines tested. In contrast, the combination of SP with various other antitumor drugs, including adriamycin, methotrexate and the vinca alkaloids and with X-irradiation did not enhance cytotoxicity. These pre-clinical in vitro studies suggest that benefit may accrue from combining SP with either 5-FU or cisplatin and provide a basis for their clinical evaluation in colo-rectal tumours or transitional cell cancer of the bladder, respectively.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line; Cell Survival; Cisplatin; Colony-Forming Units Assay; Doxorubicin; Drug Synergism; Fluorouracil; Germanium; Humans; Methotrexate; Organometallic Compounds; Spiro Compounds; Tumor Stem Cell Assay

Cooperative oncology groups usually run pilot studies of new agents or combinations concurrently with their major randomized clinical trials. A primary objective of these studies is to determine whether the new regimen should be tested further in a group-wide clinical trial. The accrual goals of such pilot studies are typically fixed in advance at between 30 and 40 patients, on the grounds that this number provides a reasonably tight confidence interval on the true response rate. Nevertheless early termination of pilot studies is often desirable either because the regimen appears inactive or because early results indicate extreme activity and justify immediate testing in a randomized study. Statistical charts are provided for early termination in both these situations. The charts are read by specifying the number of evaluable patients already accrued, the number of responses observed and the minimum true response rate, theta 0, at which the regimen would be considered active. The charts provide the posterior probability that the true response rate exceeds theta 0, that is, that the regimen is active. An additional chart that computes a 90% probability interval for the true response rate, based on the observed rate and sample size, is also provided. The use of the chart is illustrated with two examples from the Eastern Cooperative Oncology Group.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Esophageal Neoplasms; False Negative Reactions; Female; Germanium; Humans; Male; Models, Biological; Organometallic Compounds; Pilot Projects; Probability; Sampling Studies; Spiro Compounds; Time Factors

Topics: Antineoplastic Agents; Combined Modality Therapy; Drug Evaluation; Female; Germanium; Humans; Lung Diseases; Lymphoma; Male; Middle Aged; Organometallic Compounds; Spiro Compounds

Spirogermanium, a new investigational drug of novel structure currently under clinical studies in various neoplastic diseases, has revealed significant in vitro activity against chloroquine-resistant (FCB, FTA, FVO) and sensitive (FSL, FUI, FH) strains of Plasmodium falciparum. Inhibition of the growth and maturation of parasites after 36-h exposures to Spirogermanium started at concentrations ranging from 2.48 to 9.9 nM/ml. These concentrations appear to be within the range of Spirogermanium plasma levels reported in clinical studies with this drug. Since its clinical toxicities are unusually low in comparison with other anticancer drugs, our results on its in vitro activity against Plasmodium falciparum indicate Spirogermanium is an antimalarial drug of entirely novel structure, active in resistant strains.

Topics: Antimalarials; Chloroquine; Drug Resistance, Microbial; Germanium; Organometallic Compounds; Plasmodium falciparum; Spiro Compounds

Spirogermanium, an azaspirane compound, has recently had limited clinical trials using a schedule of intravenous injection one to three times every week. The observation of clinical antitumor activity and lack of myelosuppression prompted us to investigate further the clinical effects of spirogermanium administered on various schedules. A total of 52 patients with advanced metastatic tumors refractory to standard therapy were treated with spirogermanium. Three different schedules of drug administration were evaluated. Initially, a short daily IV infusion for 5 days every week was evaluated, starting with a dose of 30 mg/m2/day. A total of 22 patients received 69 courses with a dose range of 30-120 mg/m2/day for 5 days every week. The maximum tolerated dose was 100 mg/m2/day IV over 1 hr and 120 mg/m2 over 2-3 hr. In the second phase of the study, 12 patients received 41 courses of spirogermanium as a 24-hr continuous infusion for 5 days/wk at a dose of 150-375 mg/m2/day. The maximum tolerated dose was 200 mg/m2/day for 5 days. In the third phase of the study, 18 patients received spirogermanium as a continuous infusion daily for a median of 30 days (range 6-77 days) in a dose range of 100-200 mg/m2/day. The maximum tolerated dose was 150 mg/m2/day. Of the 44 assessable patients, 3 demonstrated a partial response and 3 had minor tumor regression; all responses occurred in lymphoma patients. The dose-limiting toxicity of spirogermanium was neurologic; other side effects consisted of mild anorexia, nausea and vomiting, and possible lung toxicity. There was no clear evidence of cumulative toxicity despite daily administration of spirogermanium. Our data suggest that spirogermanium can be administered daily by several different schedules, and the optimum dose depends on the infusion time and the duration of therapy. The delivery of drug by continuous infusion permitted administration of twofold higher dose levels compared to the standard IV schedules used in previous studies.

Topics: Adult; Aged; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Female; Germanium; Humans; Infusions, Parenteral; Lymphoma; Male; Middle Aged; Nausea; Nervous System Diseases; Organometallic Compounds; Ovarian Neoplasms; Spiro Compounds

Spirogermanium (NSC 192965) is a new metallic investigational anticancer drug of novel heterocyclic structure. Although its mode of action has not been fully elucidated, it appears that spirogermanium is not a phase or cell cycle specific drug and inhibits DNA, RNA and protein synthesis, the protein synthesis being the most susceptible to this agent. Spirogermanium has shown cytotoxic activity in vitro against several human tumor cell lines at concentrations (1 micrograms/ml) that were also found toxic to the cultured rat neurons. Although spirogermanium has no effect on normal bone marrow colony forming cells in mice, dogs, or man, it has revealed cytotoxic activity in vitro against human myeloid leukemia cell line K 562 at clinically achievable concentrations. These in vitro findings, indicating selective cytotoxic activity against leukemic cells suggest this drug as a candidate for clinical studies in acute and chronic leukemias. Spirogermanium has revealed activity in vivo against intraperitoneally implanted Walker 256 sarcoma, 13762 mammary adenocarcinoma, and 11095 prostatic carcinoma in rats, but no antitumor activity in vivo was found in the murine tumors used in the past by the NCI screen (L 1210 and P 388 leukemia, B 16 melanoma, Lewis lung carcinoma). Spirogermanium is remarkable for its lack of bone marrow toxicity confirmed in preclinical toxicology and clinical studies; moderate, predictable, and reversible CNS toxicity is dose-limiting. Activity in malignant lymphoma, ovarian cancer, breast cancer, large bowel cancer, and prostatic cancer was reported in the clinical studies. The drug is currently under clinical investigation against the wide spectrum of solid tumors and malignant lymphomas. The dose of 80-120 mg/m2, given by 60' infusion three times a week, is currently used and tolerated in Phase II clinical studies. The recently introduced five days continuous infusion schedule has been also under clinical investigation and the doses of 250-300 mg/m2/day are recommended for Phase II studies. Of interest are results reported in this paper of spirogermanium in vitro preferential activity against the resistant strains of Plasmodium falciparum at clinically achievable concentrations suggesting this drug as a possible new antimalarial agent of novel structure.

Topics: Animals; Antineoplastic Agents; Bone Marrow; Chemical Phenomena; Chemistry; Dogs; Drug Evaluation; Germanium; Humans; Mice; Neoplasms; Neoplasms, Experimental; Organometallic Compounds; Spiro Compounds

Topics: Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Drug Evaluation; Female; Germanium; Humans; Middle Aged; Organometallic Compounds; Spiro Compounds

Topics: Adult; Aged; Antineoplastic Agents; Drug Evaluation; Female; Germanium; Humans; Middle Aged; Organometallic Compounds; Ovarian Neoplasms; Spiro Compounds

The effect of chemotherapy on bony metastases from adenocarcinoma of the colon was investigated by quantitative skeletal imaging over a two-month interval. The quantitative skeletal imaging results correlated with conventional blood chemistry results over this time period. While chemical assay techniques furnish an average value of lesion response, the quantitative bone scan represents a method for individual lesion analysis. This methodology has the potential to provide a better understanding of metastatic bone disease therapy.

Topics: Adenocarcinoma; Antineoplastic Agents; Bone and Bones; Bone Neoplasms; Colonic Neoplasms; Diphosphonates; Fluorouracil; Germanium; Humans; Male; Middle Aged; Organometallic Compounds; Radionuclide Imaging; Spiro Compounds; Technetium; Technetium Compounds; Time Factors

Chinese hamster V79 cells were exposed to spirogermanium (SG), and their mitotic activity, population growth, plating efficiency, viability (dye exclusion), and clonogenicity were assayed. Mitotic frequency of cultures in SG decreased initially with increasing drug concentration and later plateaued at varying levels depending on drug concentration. Cultures continuously exposed to SG showed drug concentration-dependent growth inhibition, with no effect at 0.1-0.2 micrograms/ml and increasing toxicity above 0.5 microgram/ml. Cytolysis was enhanced by the simultaneous presence of amphoterocin B and by exposing cells to SG at 42 degrees C. Hypoxia protected cells from drug-induced lysis. The loss of membrane-intact cells was inversely related with population density at the time of drug exposure. Short exposures (up to 5 hours) at 20 micrograms/ml showed that cell killing was primarily through reduction of dye-excluding cells within a matter of hours and secondarily through loss of proliferative capacity. Prolonged drug contact (24 hours) at lower concentrations (1-5 micrograms/ml) accentuated the effect on clonogenicity. These results suggest that for clinical potency, prolonged drug contact may be beneficial.

Topics: Amphotericin B; Animals; Cell Division; Cell Line; Cell Survival; Chromosome Aberrations; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Germanium; Hot Temperature; Misonidazole; Mitosis; Mitotic Index; Organometallic Compounds; Spiro Compounds

The effect of spirogermanium (SG) on hematopoietic stem cells, tumor burden, and survival times was investigated in C3H mice with transplanted mammary carcinoma. Compared to normal mice, the number of hematopoietic stem cells, or colony-forming units per spleen (CFU-S), was lower in the marrow of tumor-bearing mice. Spirogermanium at 15 and 30 mg/kg was not toxic to the normal hematopoietic cells in the marrow of either normal or tumor-bearing mice. In contrast to animals treated with cyclophosphamide, SG did not decrease the tumor growth rate or prolong the survival times of tumor-bearing C3H mice. Doses of 35-40 mg/kg SG did not prolong the survival times or decrease the tumor burden of AKR/J mice with a long-passaged lymphoma. These studies demonstrate that SG has minimal inhibitory effects to the marrow of normal mice and may promote the maintenance of normal marrow cells in tumor-bearing animals. However, in two different transplanted tumor cell lines, SG did not inhibit tumor growth or prolong host survival time.

Topics: Animals; Antineoplastic Agents; Cyclophosphamide; Female; Germanium; Hematopoietic Stem Cells; Lymphoma; Mammary Neoplasms, Experimental; Mice; Mice, Inbred AKR; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasm Transplantation; Organometallic Compounds; Spiro Compounds; Spleen

In a phase I study of spirogermanium, a new azaspiran-germanium compound, 28 patients were given a multiple-dose schedule. When infused over 1 hour, the maximum tolerated single dose of this agent was greater than 120 mg/m2 but significant chronic neurologic toxicity occurred after 1-2 weeks of treatment. Patients with a poor performance status (PS) were the most likely to manifest toxic reactions. Suggested phage II dose levels for infusion treatment with spirogermanium are 120 mg/m2 for patients with a PS of 0-2 and 80 mg/m2 for patients with a PS of 3.

Topics: Adult; Aged; Antineoplastic Agents; Drug Administration Schedule; Drug Evaluation; Female; Germanium; Humans; Kidney Diseases; Male; Middle Aged; Organometallic Compounds; Spiro Compounds

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation; Female; Germanium; Humans; Middle Aged; Organometallic Compounds; Spiro Compounds

The existence of an AKR subline, AKR(Rb6.15)1A1d, with a chromosome marker provided a means to differentiate between proliferating lymphoma and normal cell populations within a single animal. An AKR(Rb6.15)1A1d lymphoma cell line has been maintained for 6 yr by serial passage in AKR/J recipients. The mice die in 7 +/- 2.0 days with evidence of extensive infiltration of the tissues by lymphoma cells. Cytogenetic analysis showed that approx. 1% of the metaphase cells in the bone marrow of mice at day 1 of the lymphoma passage were of the AKR(Rb6.15)1A1d donor-type. This increased to 54% by day 4 and 96% by day 6. The number of donor-type metaphase cells per humerus increased from 3.4 +/- 0.29 (X 10(3] at day 1 to 2.0 +/- 0.49 (X 10(5] at day 4 with a concomitant decrease in the number of non-lymphoma host-type metaphase cells. The population doubling time of donor-type metaphase cells per humerus was 12 +/- 1.4 h. At day 4, there was a significant decrease in the percentage of donor-type metaphase cells in mice that had been treated with BCNU (19.0 +/- 5.85%) or spirogermanium (38.6 +/- 5.85%) 24 h earlier. For BCNU treated animals, this also represented a decrease to 4.4 +/- 1.1 (X 10(4] donor-type metaphase cells per humerus.

Topics: Animals; Carmustine; Cell Line; Disease Models, Animal; Germanium; Karyotyping; Leukemia, Experimental; Lymphoma; Mice; Mice, Inbred AKR; Neoplasm Transplantation; Organometallic Compounds; Spiro Compounds

Lethal and other biological effects of 2-aza-8-germanspiro[4,5]decane-2-propanamine-8,8-diethyl-N,N-dimethyl dichloride (NSC 192965; spirogermanium), representing a new chemical class of compound exhibiting antitumor activity, have been studied in vitro. Survival curves for NIL 8 hamster cells were exponential with greater kill occurring with increasing drug concentrations and longer exposure times. Cytotoxicity was temperature dependent. "Quiescent" cultures were significantly less sensitive to spirogermanium than were logarithmically growing cells. These lethal effects showed no phase specificity. There was no evidence of progression delay through the cycle following spirogermanium treatment. When spirogermanium was tested against a range of human cell lines, the consistency of the values for the drug concentration required to reduce survival by 50% on the exponential part of the survival curve, derived from colony-forming assays, was most marked. The survival curves, characterized by an initial shoulder, were steep and exponential with measurements possible over only a narrow concentration range since complete cell lysis occurred at levels causing a greater than 2-log kill. Cell membrane damage by spirogermanium, as judged by dye exclusion, was progressive with time and increasing drug concentrations. Protein synthesis proved most susceptible to the drug. Spirogermanium concentrations cytotoxic to tumor cells were also toxic to cultured rat neurons, confirming the clinical neurological toxicity encountered. The precise mode of action of spirogermanium remains to be established, and these data further illustrate its apparent lack of specificity.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Cycle; Cell Line; Cell Survival; Cells, Cultured; Colonic Neoplasms; Cricetinae; Female; Germanium; Humans; Mesocricetus; Neuroblastoma; Neurons; Organometallic Compounds; Ovary; Rats; Spiro Compounds

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Evaluation; Female; Germanium; Humans; Middle Aged; Neoplasm Recurrence, Local; Organometallic Compounds; Ovarian Neoplasms; Spiro Compounds

Toxicity of single-dose spirogermanium was evaluated after iv and im administration to CDF1 mice and beagle dogs. The im LD50 in mice was approximately threefold greater than the iv LD50. The lethal dose in dogs was the same for both routes of administration, but death was delayed after im injection. Convulsive seizures occurred only after the im doses that were lethal, but they were observed after administration of iv doses that were nonlethal. Microscopic evidence of drug toxicity (necrosis and degeneration) was found in mitotically active tissues: intestinal tract, lymphoid tissue, and bone marrow. Necrosis, hemorrhage, edema, and granulation tissue were observed in the muscle injection site.

Topics: Animals; Bone Marrow; Dogs; Germanium; Injections, Intramuscular; Injections, Intravenous; Intestines; Lethal Dose 50; Lymphoid Tissue; Mice; Necrosis; Organometallic Compounds; Seizures; Spiro Compounds