Panayotis Catsoulacos

Antitumor activity of homo-aza-steroidal esters of [p-[bis(2-chloroethyl)amino]phenyl]acetic acid and [p-[bis(2-chloroethyl)amino]phenyl]butyric acid

SummaryThree new modified steroidal alkylating agents, 3β-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl)aminophenylacetate, 3β-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam-p-bis-(2-chloroethyl)aminophenylbutyrate, and 17β-hydroxy-3-aza-A-homo-4α-androsten-4-one-p-N,N-bis(2-chloroethyl)-aminophenylacetate are active in treatment of L1210 and P388 leukemias. A stereoisomer of the first compound, 3α-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13, 17-lactam-p-bis(2-chloroethyl)aminophenylacetate, was tested in L1210 leukemia. This stereoisomer, in which the alkylating agent is linked to the modified steroid in the axial position, is active only at much higher doses in L1210 leukemia. The results of testing these compounds and previous results from similar compounds allow certain conclusions to be drawn regarding structure-activity relationships. The presence of the lactam moiety is the major structural feature that confers activity in the murine leukemias. The steric arrangement of the alkylating moiety at position 3 and the hydrogen atom at position 5 influence toxicity and antileukemic activity.

Further studies on the anti-neoplastic activity of 3 β-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam {p-[bis(2-chloroethyl)amino]-phenyl}acetate (NSC 290205)

Abstract The modified steroidal alkylating agent 3β-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam { p -[bis(2-chloroethyl)amino]phenyl} acetate (NSC 290205) is active in treating the LX-1 lung and MX-1 breast xenografts as well as a number of rodent tumors. Of 13 tumors tested, activity has been shown in 10 systems. Two systems have not received adequate testing and negative results were recorded in 1 system.

Effect of a ▵5-Homo-Aza-Steroidal Ester in P388 and L1210 Murine Leukemias

3β-Hydroxy-13α-amino-13,17-seco-5-androsten-17-oic-13,17-lactam p-N, N-bis-(2-chloroethyl)-amino phenylacetate gives results in P388 and L1210 leukemias in mice, by the intraperitoneal route of administration.

Comparison of Current Alkylating Agents with a Homo-aza-Steroidal Ester for Antineoplastic Activity

The modified steroidal alkylating agent, 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-bis(2-chloroethyl)aminophenoxyacetate++ + has been tested against L1210 and P388 leukemias, and Lewis lung cancer, on DNA synthesis of EAT, L1210, P388, and BHK cell cultures, and on the induction of sister chromatid exchange. Comparable studies in vivo and in vitro were also done with p-bis(2-chloroethyl)aminophenoxyacetic acid, cyclophosphamide, melphalan, and chlorambucil.

Activity of 13β–Hydroxy–13α–amino–13,17-seco– 5α–androstan–17–oic–13,17–lactam–p–bis(2–chloro–ethyl)aminophenoxyacetate (NSC 294859) on Experimental Animal Tumor and Leukemia Systems

3 β -hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam- p -bis(2-chloroethyl)amino-phenoxyacetate, a modified steroidal alkylating agent, is active in the

Induction of cytogenetic damage by modified steroidal derivatives of p-bis(2-chloroethyl)aminophenylacetic acid in human lymphocytes.

The effect of modified steroids, containing alkylating agents, on SCE rates and on cell kinetics in cultured human lymphocytes was studied. The homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenylacetic acid (ASE) was found to be the most effective in causing markedly increased SCE rates and cell division delays. The androsterone ester of p-bis(2-chloroethyl)aminophenylacetic acid (AE-CAPA) was found to be next in order of effectiveness with the lactone ester (LE-CAPA), chlorambucil ester 3 beta-hydroxy-13a-amino-13,17-seco-5a-androstan-17-oic-13,17-lactam (CBC-HAAL) and chlorambucil (CBC) following. p-Bis(2-chloroethyl)aminophenylacetic acid (CAPA) had only a small effect and 3 beta-hydroxy-13a-amino-13,17-seco-5a-androstan-17-oic-13,17-lactam (HAAL) had no effect at all. A correlation between potency for SCE induction, effectiveness in cell division delay and previously established antitumor activity of these drugs was observed.

Response of Transplantable Tumors in Mice and of Macromolecular Synthesis to 17β-Acetamido-3-aza-A-homo-4α-androsten-4-one

17β-acetamido-3-aza-A-homo-4α-androsten-4-one has cytostatic activity against Ehrlich ascites tumor, 11210, and P388 leukemias in mice when administered in-traperitoneally. The effect of the homo-aza-steroid on the incorporation of radioactive precursors to DNA and RNA of 12210 leukemia cells was investigated. It was found that treatment of cells with 12.5 fig/ml of the drug for I hour inhibited DNA synthesis by 81%. This was partly because the drug affected the radioactive thymidine pool in the cell. The inhibitory effect was found to be reversable. The incorporation of [3H]thymidine into DNA was lower when cells were incubated in the presence of S9 mix. It was also found that the same compound inhibited RNA synthesis by 67%.

Synthesis of a New nor-Aza-Steroidal Ester of p-N,N-bis-(2-Chloroethyl)aminophenylbutyric Acid and in vitro Study of Its Mutagenicity and Clastogenicity

A new nor-aza-steroidal ester of chlorambucil has been synthesized. The study of the mitotic index in CHO and HeLa cells treated with this compound showed that it may be a cytostatic drug. It was also found that treatment of CHO cells with a dose as low as 5 micrograms/ml induces a large number of sister chromatid exchanges. A great number of abnormal metaphases has been observed when CHO cells were treated with the compound at a dose of 25 micrograms/ml. When the compound was tested in the Ames/Salmonella microsome assay, it was found to be mutagenic in strains TA100 and TA1535, both with and without metabolic activation.

Synergistic induction of cytogenetic damage by the homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenylacetic acid in combination with caffeine in human lymphocytes in vitro and in Ehrlich ascites tumour cells in vivo

We studied the effects of caffeine alone or in combination with homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenylacetic acid (ASE, NSC 290205) on the frequency of SCEs and lymphocyte proliferation kinetics. Caffeine was found to act synergistically with ASE on the induction of SCEs when the two components were administered in combination. Caffeine was also found to act synergistically with ASE in inducing cell-division delays. Enhanced cytogenetic damage by ASE was observed when Ehrlich ascites tumour cells (EAT cells) were exposed in vivo to caffeine. ASE alone or in combination with caffeine caused a dose-dependent increase in SCE rates and cell-division delays. SCEs were demonstrated in EAT-bearing mice, by the i.p. injection of BrdUrd adsorbed onto activated charcoal, 1 h after the i.p. injection of ASE and/or caffeine.