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PubMed1990

In vitro and in vivo anticancer activity of mitozolomide and sparsomycin in human tumor xenografts, murine tumors and human bone marrow.

The colony formation in agar of human tumor xenografts, of murine tumors and of human bone marrow was used as a test system to determine the in vitro activity of the two novel cytostatic agents, mitozolamide and sparsomycin. Mitozolomide was additionally studied in vivo in nine human tumor xenografts. The comparison of in vitro/in vivo activity allows an assessment of the relevant in vitro dose based on in vivo pharmacological behavior of a compound. Both compounds showed clear dose/response effects in vitro. A dose of 3 micrograms/ml mitozolomide, given by continuous exposure, was active (colony number of test less than 30% of the control group) in 12/42 (29%) human tumor xenografts as well as in the four murine tumors, P388, L1210, B16 melanoma and colon carcinoma 38, whereas the two human bone marrows showed no significant suppression of the ability to form colonies in culture. The comparison of in vitro with in vivo activity suggests that the in vitro dose of 3 micrograms/ml corresponds best to the activity observed in animal experiments. The highest activity was observed in small-cell cancer of the lung (4/5), followed by melanomas (2/7) and non-small-cell cancer of the lung (2/9). Furthermore, activity was found in a cancer of the large bowel, stomach, breast and in one sarcoma. In the treatment of nine human tumor xenografts growing subcutaneously in nude mice, mitozolomide effected a complete or partial remission in 6 out of 9 tumors. In comparison to standard drugs mitozolomide is one of the most effective compounds in these tumors. These data indicate that mitozolomide possesses potent broad-spectrum activity in human tumor xenografts. Sparsomycin (0.1 micrograms/ml, continuous exposure) was active in 11/46 (24%) human tumor xenografts and in 4/5 of the murine tumors, whereas the colony-forming capacity of four human bone-marrows showed no inhibition, suggesting that this dose level may be the relevant in vitro dose. However, the high in vitro activity in murine tumors is incompatible with the in vivo activity. In mice the only responsive tumor was leukemia P388, whereas the L1210, B16 melanoma and colon carcinoma 38 were resistant. At the dose level of 0.03 microgram/ml only 3/30 (10%) of the human tumor xenografts were sensitive. In an earlier clinical phase I study the dose-limiting adverse effect was eye toxicity and not bone-marrow suppression.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Evaluation of 'cypenhymustine', a new anticancer compound, in murine tumour models.

'Cypenhymustine', 3-[2-[bis(2'-chloroethyl)-amino] ethyl]-5,5- tetramethylenehydantoin, has been synthesised as a potential analog of spiromustine (NSC 172112). The LD50 value was determined in Swiss male mice and found to be 65.0 mg/kg by single i.p. injection. In in vivo screening experiments, three parameters, namely, ascites cell count, ascites fluid measurement and increase in life span (ILS) of drug-treated over control Swiss mice were studied in three murine ascites tumours namely Ehrlich ascites carcinoma (EAC), sarcoma-180 (S-180) and Dalton's lymphoma (DL). Cypenhymustine exhibited a very high percentage of inhibition of both the ascites cell and fluid in these models and also displayed excellent reproducible ILS activity (ILS values of 151 in EAC, 157 in S-180 and 181 in DL at the optimum dose of 3 mg/kg for days 1-7 treatment following tumour transplant on day 0) having a 'curative' effect (1-2 animals: 6 having > 60 days survival rate). The chemical alkylating activity has been compared with spiromustine and another antitumour agent namely nor-HN2.

Animals↗
PubMed1975

Cellular and biochemical aspects of growth retardation in rat fetuses induced by maternal administration of selected anticancer agents.

Single ip injections of 600 mg/kg 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DIC) and 900 mg/kg 5-[3,3-bis(2-chlorethyl)-1-triazeno]-imidazole-4-carboxamide (BIC) were given to pregnant Wistar rats at day 12 and the animals were killed 4 h after injection and at days 13-17 of gestation. Fetal tissues were used to determine total DNA, RNA, and protein and the data used to derive cell number and cell weight, RNA, and protein/cell. Both compounds reduced total fetal body weight, DNA, RNA, and protein but reduction of RNA by BIC was not statistically significant. These effects were observed 4 h after injection, increased with age (days 13-17), and were 3-4 times greater for DIC than BIC. By using the value of 6.2 mumug DNA/cell, cell number and per-cell values for weight, RNA, and protein, and weight: DNA, RNA:DNA, and protein:DNA ratios were computed. The per-cell values and ratios in the DIC-exposed animals were 8-44% greater and in BIC-treated animals 0-11% greater than control animals of the same gestational age. Percentage of body water was the same in the experimental and control animals. The differences in DNA, RNA, and protein are believed to be related to drug-induced growth retardation incident to total fetal DNA reduction resulting in diminished cell number.

Animals↗
PubMed2005

Research on the anti-tumour effect of steroid lactam alkylator (NSC-294859) in comparison with conventional chemotherapeutics in malignant melanoma.

Evidence indicating that hybrid steroid compounds of anti-cancer agents produce reduced toxicity, significantly lower than the cytotoxic components alone, and increased anti-cancer activity has prompted the design and development of such steroids, mostly alkylating esters. We investigated the in-vitro and in-vivo activity of a homo-aza-steroidal alkylating ester (HASE), in comparison with dacarbazine (DTIC), cisplatin (CPDD), carmustine (BCNU) and semustine (MeCCNU), in the treatment of malignant melanoma. Cytotoxicity was assessed in vitro by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using a panel of six human malignant melanoma cell lines, with or without the presence of rat liver microsome assay. B16 melanoma-bearing mice were used to evaluate in vivo the anti-tumour activity of the tested compounds. In all cases of in-vitro screening, HASE displayed a significantly higher (P<0.0001) cytostatic and cytotoxic effect than DTIC, BCNU and MeCCNU, but produced significantly lower (P<0.0001) activity than CPDD. HASE exhibited a significantly smaller range than CPDD between concentration levels that produced growth arrest and those that induced a cytotoxic effect against melanoma cells in vitro. The anti-tumour activity of HASE in B16 melanoma-bearing mice, as determined by tumour growth rate inhibition (<42%) and percentage survival prolongation (treated versus control, 167%), was significantly superior (P<0.001) to that achieved by DTIC, BCNU and MeCCNU and was equal to that of CPDD. HASE exhibited a toxicity similar to that of DTIC, BCNU and MeCCNU, but significantly lower than that of CPDD. It can be concluded that HASE displays significant in-vitro and in-vivo activity in the treatment of melanoma.

Animals↗
PubMed1992

Site-dependent differences in sensitivity of LOX human melanoma tumors in nude rats to dacarbazine and mitozolomide, but not to doxorubicin and cisplatin.

Three model systems involving LOX human malignant melanoma cells in nude rats were used to compare the chemosensitivity of tumors growing in different tissues. Groups of 4-18 rats with either s.c. xenografts, lung tumor colonies, or bone metastases were treated with cisplatin, doxorubicin, dacarbazine, or mitozolomide. The antitumor effect in the s.c. model was expressed as specific growth delay, and in the experimental metastasis studies as relative increase in life span (RILS), calculated on the basis of observed disease-free survival. Cisplatin had a moderate but significant effect on the progression of LOX tumor growth in all three systems. Doxorubicin was clearly more efficacious, but for both drugs tumor-free survivors were rare or absent. Importantly, for each of the compounds the levels of response were roughly the same in all three models, with specific growth delay and RILS values in the range of 0.2-0.3 for cisplatin and 0.5-0.9 for doxorubicin. In contrast, a significant site-dependent difference in sensitivity of the LOX tumors was observed for two alkylating agents. Thus, dacarbazine, which temporarily caused complete regression of s.c. xenografts (specific growth delay = 21.0), showed a moderate activity in the lung tumor model (RILS = 1.0) but had only a limited effect (RILS = 0.4) on bone metastases. Mitozolomide gave a curative effect in 6 of 10 animals with s.c. and in 4 of 4 animals with lung tumors, whereas in the bone metastasis model it was only slightly superior to doxorubicin (RILS = 1.1). In preliminary attempts to elucidate the underlying mechanisms, no site-dependent differences in drug distribution and in two cellular detoxifying systems were detected. The data demonstrate the usefulness of the LOX models for studying the clinically relevant problem of site-dependent tumor response to chemotherapy.

Animals↗
PubMed1991

Comparison of half-lives and cytotoxicity of N-chloroethyl-4-amino and N-mesyloxyethyl-benzoyl compounds, products of prodrugs in antibody-directed enzyme prodrug therapy (ADEPT).

The synthesis of two novel drugs, 4-[bis[2-(mesyloxy)ethyl]amino]benzoic acid (7) and 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]benzoic acid (8) is described here. They are the active drugs of two prodrugs (9 and 10) designed for use as anti-cancer agents. The prodrugs (9, 10 and 11) were made as a series of compounds which are bifunctional alkylating agents in which the activating effect of the ionized carboxyl function is masked through an amide bond to a glutamic acid residue. These relatively inactive prodrugs were designed to be activated to their corresponding alkylating agent active drugs (7, 8 and 12 respectively) at a tumour site by prior administration of a monoclonal antibody conjugated to a bacterial enzyme. This system is called antibody-directed enzyme prodrug therapy (ADEPT). The chemical half-lives of the prodrugs and their active drugs were measured in order to determine their relative reactivities. The half-lives ranged from 21 to 324 min for the active drugs and from 42 to 1158 min for the prodrugs. The viability of two different tumour cell lines was monitored with each active drug and prodrug. The IC50 values varied from 65 to 625 microM for the active drugs: no IC50 values could be obtained for the prodrugs, using a rapid incubation procedure. Each in vitro technique demonstrated the ability of the glutamic acid moiety to deactivate the drugs, forming effective prodrugs.

Antibodies, Monoclonal↗
PubMed1981

Effects of inducer of liver drug-metabolizing enzyme on blood level of active metabolites of cyclophosphamide in rats and in cancer patients.

It was already reported that a masked compound, cyclophosphamide (Endoxan, EX) undergoes the first step metabolism by a drug-metabolizing enzyme in liver microsomes, cytochrome P-450. By pretreatment with phenobarbital as an inducer of P-450, the maximum blood level of active metabolites of EX (normustard-like substances) in normal rats was 2.3 times higher than that in non-treated rats, in conformity with the increase in amount of liver P-450 and in alkylating activity of EX. In YS (Yoshida sarcoma)-bearing rats, the value of liver P-450 went down day by day to 1/2 on the 4th day after inoculation, but it remained normal when animals were pretreated with phenobarbital. In parallel with this, the blood level of normustard-like substances after EX administration was normal or showed a tendency toward increase. In 11 clinical cases pretreated with phenobarbital, the blood level of normustard-like substances 1 to 3 hr after EX administration, at the time when it reaches the peak was 1.5 times higher on an average than that in cases without pretreatment.

Adult↗
PubMedDate not supplied

Evaluation of barrier creams against sulphur mustard. I. In vitro studies using human skin.

The purpose of this study was to assess the effectiveness of a range of passive and reactive barrier cream formulations against the chemical warfare agent sulphur mustard (SM) using an in vitro diffusion cell system containing human skin. In general, proprietary formulations were relatively effective under occluded conditions, but ineffective under unoccluded conditions. For example, SM skin absorption rates through occluded control and Stokoderm pre-treated skin were 538 +/- 193 and 200 +/- 51 microg x cm(-2) x h(-1), respectively (p < 0.05). Under unoccluded conditions, control and Stokoderm pre-treated skin absorption rates were 4.41 +/- 1.90 and 36.84 +/- 15.19 microg x cm(-2) x h(-1) (p < 0.05). Novel (perfluorinated) barrier creams were generally more effective under unoccluded conditions; pre-treatment with one formulation led to an 18-fold reduction in skin absorption rate and reduced the total amount of SM penetrated by 95% of the applied dose. Several proprietary formulations also had adverse effects on the effectiveness of the skin decontaminant fuller's earth. The rate (Jss) and total amount (percentage of dose) of SM absorbed through the skin were deemed to be independent parameters of barrier cream performance. These data indicate that (1) perceived conditions of use, (2) compatibility with existing protective equipment and (3) the rate and extent of SM skin absorption must all be taken into account when evaluating barrier creams in vitro.

Administration, Cutaneous↗
PubMed1999

Preclinical activity of 17 beta-[N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-L-alanyl]-5 alpha-dihydrotestosterone (E91) against tumour colony forming units and haematopoietic progenitor cells.

E91 (17 beta-[N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-L-alanyl]-5 alpha-dihydrotestosterone) (CNC-ala-DHT) is a newly synthesised alkylating compound consisting of N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-L-alanine (CNC-ala) as the alkylating moiety and of 5 alpha-dihydrotestosterone (DHT) as a steroid carrier molecule. We studied the antitumour activity of E91 (final concentrations: 0.1, 1, 10 and 30 mumol/l) against freshly explanted human tumours, using an in vitro soft agar cloning system. A total of 54 tumour samples was evaluated using 1 h-exposure and 51 tumour specimens were studied using a continuous exposure for 21-28 days. In addition, the compound's activity was compared with other clinically used anticancer agents. After short-term exposure, 49 of 53 evaluable specimens (92%) had adequate colony formation, as compared with 49 of 50 (98%) after long-term exposure. After short-term exposure, E91 exhibited only marginal antitumour activity. However, in long-term exposure experiments, E91 had marked and concentration-dependent antitumour activity (P < 0.001). At concentrations of > 10 mumol/l, E91 was as active as the other clinically used antineoplastic agents and at 30 mumol/l, E91 was significantly more active than 5-fluorouracil (P = 0.041). E91 showed activity against a wide spectrum of tumour types. The highest activity was observed against colorectal carcinomas (3/4 tumour specimens inhibited at 30 mumol/l). Sensitivity was also high remarkable in breast cancer specimens with 3/6 specimens inhibited at 30 mumol/l. In vitro myelotoxicity was less than that of doxorubicin. At 30 mumol/l, E91 induced a reduction of colony forming units-granulocyte macrophage (CFU-GM) to only 53% of control and of CFU-GEMM to 20% of control. We conclude that because of broad activity and reduced myelotoxicity further clinical development of E91 appears warranted.

Antineoplastic Agents↗
PubMed1997

Estimation of the haematological toxicity of minor groove alkylators using tests on human cord blood cells.

We evaluated the myelotoxicity and the anti-tumor potential of tallimustine, three of its analogues and carzelesin, with melphalan as reference substance. Tallimustine was tested by clonogenic assays on both human bone marrow (BM) and cord blood (hCB) cells, the other compounds on hCB only. The degree of inhibition of the haemopoietic progenitors GM-CFC, CFC-E and BFU-E was evaluated after exposure to different concentrations. The same schedules were tested on five tumour cell lines. We found that the dose-response curves for tallimustine on BM and hCB cells were similar. Carzelesin was shown to be the most potent of the substances tested and to be the one with the best in vitro therapeutic index; of the distamycin analogues, the one bearing an alpha-bromoacrylic group (FCE 25450) had the best index. For melphalan, tallimustine and carzelesin, the concentration inhibiting the growth of 70% of progenitor cells in vitro (ID70) was similar to the concentrations found in the serum of patients treated at the maximum tolerated dose (MTD). We conclude that hCB cells may be used instead of BM cells for in vitro myelotoxicity tests. Therapeutic indexes can be extrapolated from this model and could help in selecting the most promising analogue for further clinical development. The in vitro-active concentrations are similar to myelotoxic concentrations in patients, suggesting a predictive value for the assay.

Adult↗
PubMed1990

Modulation of cytosolic sexual steroid receptors in autochthonous methylnitrosourea-induced rat mammary carcinoma following application of 2-chloroethylnitrosocarbamoyl-L-alanine linked to oestradiol or dihydrotestosterone.

This study concentrated on the influence of 2-chloroethylnitrosocarbamoyl-L-alanine (CNC-L-ala) linked to oestradiol (CNA-L-ala-E2) or dihydrotestosterone (CNC-L-ala-DHT) in position 17 of the respective steroid hormone on tumour growth and receptor kinetics of methylnitrosourea-induced rat mammary carcinoma. Both compounds almost completely arrested logarithmically growing mammary carcinoma of Sprague-Dawley rats: in the first week CNC-L-ala-E2 blocked the growth of these tumours by 92% compared to untreated control animals while, in animals treated with the physically equimolar mixture of CNC-L-ala and oestradiol (positive control), tumour growth was inhibited by 51% only. CNC-L-ala-DHT arrested the tumour growth in the first week by 95%, while the respective positive control (CNC-L-ala plus dihydrotestosterone) effected a growth inhibition of 71% compared to the untreated control. These results correlate well with the influence of both drugs on the cytosolic receptor content of sexual steroid hormones in the tumours. CNC-L-ala-E2 depleted the content of oestradiol receptors and kept it down for a week, while concomitantly the content of progesterone receptors increased considerably and that of androgen receptors showed a short-lived decrease. CNC-L-ala-DHT depleted androgen receptors as well as progesterone receptors. The content of androgen receptors remained low for a week, while that of progesterone receptors recovered within 8 days. The content of oestrogen receptors showed a moderate decrease.

Animals↗
PubMedDate not supplied

Morphological and cytogenetical changes in HR-18 rat ascites cells after in vitro 3-[bis(2-chloroethyl)amino]-4-methylbenzoic acid (NSC-146171; IOB-82) administration.

A bifunctional alkylating agent, 3-[Bis(2-chloroethyl) amino]-4-methylbenzoic acid (NSC-146171; IOB-82) was administered in HR-18 rat ascites cell cultures (which presented 2 morphologic cellular types: A and B type cells, genetically, 2 cellular populations having 41-45 and 85-86 chromosomes and cells with high ploidy), and the morphological and cytogenetical effects were related to the compound concentration. Thus, 24 h after IOB-82 administration in small doses (3.62 X 10(-4) micron/ml), important morphological changes were observed: nuclear changes (denuded nuclei, pyknosis) and cytoplasmic alterations (breaks at the exoplasm level, followed by cytoplasmic extrusions in extracellular spaces, cytoplasmic vacuolization). In addition to these changes, other abnormalities were observed when IOB-82 was administered in large doses (3.62 X 10(-3) micron/ml), i.e., nuclear changes (nuclear residues, granulation of the nuclear material and spreading of the nuclear content into cytoplasm) and cytoplasmic alterations (cytoplasmic shades and accentuated cytoplasmic vacuolization). Generally, the large A-type cells were more affected. Twenty-four h after IOB-82 treatment (with small or large doses), the chromatid and chromosome aberrations (gaps, breaks, deletions, fragments) were also observed. These aberrations were more numerous when IOB-82 was administered in large doses. Both morphological and cytogenetical changes indicate that the effect of IOB-82 could be radiomimetic. Changes produced and their incidence appear to depend on the concentration of IOB-82 employed and the morphological type of ascites cells. These are expressed in terms of multiple abnormality production in these cells. IOB-82 treatment produced changes in chromosome numbers and especially the disappearance of polyploid cells and cell populations with 85-86 chromosomes. These results indicate a possible correlation between the increased sensitivity of HR-18 rat ascites cells and changes in ploidy.

Animals↗
PubMed1990

Sensitivity of chronic myeloid leukemia hemopoietic progenitors to PTT-119 in combination with human recombinant interferon alpha and gamma.

PTT-119, a new synthetic alkylating compound, has shown a marked "in vitro" inhibitory effect on chronic myeloid leukemia (CML) granulo-monocytic precursors (CFU-GM) at doses greater than 5 micrograms/ml. Based on previous experiences of synergistic associations between alkylating drugs and biological modifiers, we tested the effects of low doses of PTT-119 (from 0.1 to 1 microgram/ml) in concert with alpha, gamma, or alpha + gamma interferons and compared to IFNs alone, in order to investigate an alternative choice for treatment of CML patients in chronic phase. Our results showed a significantly higher CFU-GM cloning inhibition after addition of 100 or 1,000 U/ml of alpha IFN to 0.1 microgram/ml PTT-119 (from 39.6% +/- 26.6 SD to 80.7% +/- 10 SD and 91.5% +/- 8 SD, respectively), while gamma IFN resulted in only a slight increase in colony growth inhibition when compared to the drug used alone. The association of alpha plus gamma IFN coupled with PTT-119 treatment did not significantly improve the results observed after exposure of leukemic progenitors to PTT-119 and alpha IFN alone. We conclude that a combined treatment with PTT-119 and IFN is probably worth testing both for purging methods before autologous bone marrow transplantation and for in vivo administration in chronic myeloid leukemia.

Antineoplastic Agents↗
PubMed1982

Quantitative forward-mutation specificity of mono-functional alkylating agents, ICR-191, and aflatoxin B1 in mouse lymphoma cells.

We have analyzed forward-mutation specificity in S49 mouse T lymphoma cells. Our criteria of specificity were based upon relative mutabilities of a panel of 3 genetic markers: resistance to 6-thioguanine (6TGr), dibutyryl cAMP (bt2cAMPr), and ouabain (OUAr). We tested 2 monofunctional alkylating agents, ethyl methane-sulfonate (EMS) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and 2 heterocyclic compounds, ICR-191 and aflatoxin B1 (AFb1). AFB1 was activated with rat-liver microsomal S9 plus cofactors. Expression-time lags of each genetic marker ranged from 2 days of OUAr mutations to 6 and 8 days for bt2cAMPr and 6TGr cells, with stable induced mutant fractions thereafter. The relative activity of each agent for each marker was assessed on the basis of its mutagenic efficiency at equitoxic doses. Specificity differences between the agents were determined by taking ratios of mutagenic efficiencies (RME) for the 3 possible pairs of markers. From these quantitative correlations and other data we conclude that both MNNG and EMS induce ouabain resistance (and probably bt2cAMPr and 6TGr) by similar mechanisms, almost certainly base substitutions. In contrast, ICR-191 and AFB1 are respectively less than 2 and 3% as efficient as MNNG for OUAr mutant induction relative to the activity of each agent for 6TGr mutagenesis. We infer that ICR-191 and AFB1 very rarely cause base substitutions in S49 cells, but that their activities are consistent with production of deletions, insertions or chromosomal aberrations. S49 cells demonstrate an unusually high specificity of mutagenesis at the OUAr locus compared to several other rodent cell lines. Thus, this panel of markers in S49 cells can be used as a sensitive, reliable screening system for mutagen detection and to discriminate among major classes of mutagenic mechanisms.

Aflatoxin B1↗
PubMed1995

O6-alkylguanine-DNA alkyltransferase attenuates triazene-induced cytotoxicity and tumor cell immunogenicity in murine L1210 leukemia.

Methylating and chloroethylating triazene compounds (TZCs) are effective antitumor agents in murine leukemias and can induce the appearance of novel antigens in leukemic cells (chemical xenogenization). Recently, it has been shown that TZCs might have a role in the treatment of patients affected by acute myelogenous leukemias that express low levels of the DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase (OGAT). In this report, we have evaluated the role of this DNA repair enzyme in the leukemic cell response to the xenogenizing and cytotoxic properties of TZCs. OGAT-deficient murine leukemic L1210 cells were transfected with a recombinant ecotropic retrovirus containing the coding region for the human OGAT protein. Selected clones expressed the human OGAT transcript and had greatly increased OGAT activity. Compared to OGAT-deficient cells, OGAT-expressing cells were considerably more resistant to the xenogenizing properties of 1-(p-chlorophenyl)-3,3- dimethyl-triazene, measured in terms of leukemia graft rejection, and were less susceptible to the cytotoxic activity of the TZCs 8-carbamoyl-3-methyl-imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one and 8-carbamoyl-3-(2-chloroethyl)imidazo [5,1-d]-1,2,3,5-tetrazin-4(3H)-one. These data suggest that methylation of the O6 position of guanine is involved in the appearance of increased tumor immunogenicity after exposure to methylating TZC and that OGAT is able, at least in part, to counteract the cytotoxic effects of methylating and chloroethylating agents.

Animals↗
PubMedDate not supplied

Therapeutic efficacy of two different cytostatic-linked phosphonates in combination with razoxane in the transplantable osteosarcoma of the rat.

Two new compounds, 4-[4-[bis-(2-chloroethyl)-amino-]phenyl]-1- hydroxybutane-1,1-bisphosphonic acid (BAD) and aminotris-(methylenephosphonato)-diamminoplatinum(II) (ADP) that both have cytostatic and osteotropic properties, have shown good therapeutic efficacy against an osteosarcoma which metastasizes and kills by lung metastases. We therefore combined each of these drugs with the antimetastic agent razoxane. Razoxane (20 mg/kg i.p., 5 days/week for 6 weeks) was administered in combination with either BAD (30 mg/kg i.p.) or ADP (37.5 mg/kg i.v.) twice weekly for 3 weeks. Tumour volumes, body weight, survival time and occurrence of metastases were recorded, in addition to the measurement of the metastasis area compared to the total lung area in serial histological lung samples. In both experiments, razoxane effected a significant increase in life span while being ineffective in tumour inhibition. Razoxane in combination with BAD displayed an enhanced anticancer activity which was not significant. ADP had a good antineoplastic activity and a large increase in survival time (144 per cent ILS). Razoxane used in combination with ADP did not influence antitumour efficacy. Median survivals of both ADP-treated groups were significantly longer than the razoxane-treated group. Analysis of the lung metastasis area showed a maximum of 57 per cent for the controls while all treated groups occupied a lesser area. The lowest metastases area was found with the combination treatment BAD + RAZ (18 per cent). This was considered an antimetastatic effect, while ADP treatment effected a time delay only. No change in metastatic pattern was observed in any of the treatment groups. Histological examination showed no effect on the capillaries in the proliferating region of the tumours that could account for the lower occurrence of metastases.

Animals↗