1061 ation between Yersinia antibodies and the A, B, C, and D segregant series of the HLA’" or thyroid autoantibodies has been demonstrated.2But indirect immunofluorescence reveals a high frequency of thyroid cell-membrane directed antibodies in sera with Yersinia agglutinating antibodies." This, when linked to the evidence of humoral and cellular immunity to Yersinia antigen in thyroid patients without clinical signs or history of Yersinia infection, seems to favour the theory of a cross-reaction between antigenic components of the thyroid and Yersinia. Medical Department of Endocrinology F, Herlev Hospital; Division of Clinical Immunology,
Medical Department TA, Rigshospitalet; and
Department of Rheumatological Disease, Gentofte Hospital, Copenhagen, Denmark
KARINE BECH OLE CLEMMENSEN JORGEN HANNOVER LARSEN GUNNAR BENDIXEN
DEOXYCYTIDINE AND LETHAL DOSES OF CYTARABINE IN ADVANCED MURINE LEUKÆMIA
SiR,-Deoxycytidine (CdR) is the antagonist of cytarabine (cytosine arabinoside), diminishing both its toxic and antitumour
effects.’-10 Oral administration of CdR
to
mice simul-
taneously with intraperitoneal injections of cytarabine reduced the toxic manifestations of cytarabine and suppressed its lethal effect. Analysis of the mechanism underlying the effect of the CdR plus cytarabine combination in various haematopoietic cell lines showed that in the bone-marrow of CdR-protected animals lymphocytes remained unprotected (e.g., their count 11. Lidman, K., Eriksson, U., Fagraeus, A., Norberg, R. Lancet, 1974, ii, 1449. 1. Biro, V., Goldenberg, D. M. Chemotherapy, 1971, 16, 29. 2. Buchman, V. M., Vyshinskaya, G. V., Belyanchikova, N. I., Svet-Moldavsky, G. J. Vopros. Oncol. (in the press). 3. Buchman, V. M., Lichinitser, M. R., Svet-Moldavsky, G. J., Mkheidze, D. M. Bull. Exp. Biol. Med. (in the press). 4. Chaube, S., Kreis, W., Uchida, K., Murphy, M. L. Biochem. Pharmac.
1968, 17, 1213. Dollinger, M. R., Burchenal, J. H., Kreis, W., Fox, J. J. ibid. 1967, 16, 689. Evans, J. S., Mengel, G. D. ibid. 1964, 13, 989. Fisher, D. S., Cassidy, E. P., Welsh, A. D. ibid. 1966, 15, 1013. 8. Papac, R. J., Calabresi, P., Hollingworth, J. W., Welch, A. D. Cancer Res. 1965, 25, 1459. 9. Papac, R., Creasey, W. A., Calabresi, P., Welch, A. D. Proc. Am. Ass. 5. 6. 7.
10.
Cancer Res. 1965, 6, 50. Schrecker, A. W., Mead, J. A. R., Urshel, 15, 1443.
EFFECT OF
cdR
M. U. Biochem. Pharmac.
were
and leukaemias. The ascitic form of L1210 leukaemia was induced by weekly transplantation of tumour cells into the peritoneal cavity of DBA/2 mice. The recipients of L1210 leukaemia were adult DBA/2 females and BDF-I hybrid males weighing 22-28 g. All mice were obtained from the Stolbovaya breeding farm of the A.M.S. of the U.S.S.R. We used ’Cytosar’ (lot 217BS, no. tumours
7309, Upjohn, Kalamazoo, Michigan) and 2’-deoxycytidine hydrochloride (lot no. 04015, Reanal, Hungary). The drugs were dissolved in physiological saline solution. In all experiments the treatment was started no earlier than on day 5 after tumour-cell inoculation into mice. Doses and days of inoculation are indicated in the table. The drugs were inoculated intraperitoneally or given orally in 0.2ml volume. CdR was administered orally via a bent metal probe. CdR alone had neither toxic nor anti-tumour effects (see table). The schedule of cytarabine treatment was lethally toxic. At necropsy mice which had received cytarabine alone had no subcutaneous tumours at the site of L1210 cell inoculation; the median spleen and liver weights were much smaller than in healthy non-leukaemic animals (not indicated in the table). CdR inoculation suppressed toxicity of cytarabine, and the combination produced a strong antitumour effect on L1210 leukaemia (see table). In experiment 5 CdR suppressed the development of cytarabine toxicity in 12 of 19 mice; in other experiments all mice escaped toxicity. Thus the CdR/cytarabine combination was effective in the treatment of L1210 leukaemia provided that the cytarabine schedule was lethally toxic. These results and our earlier morphological study of the effect of the CdR/cytarabine combination on haemopoiesis in the bone-marrow from normal mice support the view that the selective effect might be associated with the absence of protection of lymphoid cells. These data should encourage clinical trials of the CdR plus cytarabine combination in the treatment of acute and chronic lymphoid leukaemia, for other forms of neoplasia, and, perhaps, for autoimmune processes as well. VLADIMIR M. BUCHMAN GEORGE J. SVET-MOLDAVSKY MISHA R. LICHINITSER Cancer Research Centre, Moscow 115478, U.S.S.R. DEMURI M. MKHEIDZE
ON EFFICACY OF TOXIC SCHEDULES OF CYTARABINE ADMINISTRATION IN MYELOBLAST AND
LYMPHOBLAST
* 10’ ascites cells of L1210
1966,
not differ from that in mice receiving the antimetabolite alone).2 These data suggested that this combination might result in the selective suppression or eradication of lymphoid
did
L1210
LEUKAEMIA
implanted subcutaneously on day 0 into DBA/2 females in expt.
1 and BDF-I males
in
expts. 5, 6.
1 M.s.r.-median survival-time.
tIn expt. 2 seven mice died of toxicity and form a separate subgroup. From 10 to 13 days they received the drugs In all experiments the drugs were inoculated 4 times/day with an interval of 2 h between injections. § I hese figures do not include 10 mice which have lived for over 50 days.
in
10 times smaller doses.
Medical Department TA, Rigshospitalet; and
Department of Rheumatological Disease, Gentofte Hospital, Copenhagen, Denmark
KARINE BECH OLE CLEMMENSEN JORGEN HANNOVER LARSEN GUNNAR BENDIXEN
DEOXYCYTIDINE AND LETHAL DOSES OF CYTARABINE IN ADVANCED MURINE LEUKÆMIA
SiR,-Deoxycytidine (CdR) is the antagonist of cytarabine (cytosine arabinoside), diminishing both its toxic and antitumour
effects.’-10 Oral administration of CdR
to
mice simul-
taneously with intraperitoneal injections of cytarabine reduced the toxic manifestations of cytarabine and suppressed its lethal effect. Analysis of the mechanism underlying the effect of the CdR plus cytarabine combination in various haematopoietic cell lines showed that in the bone-marrow of CdR-protected animals lymphocytes remained unprotected (e.g., their count 11. Lidman, K., Eriksson, U., Fagraeus, A., Norberg, R. Lancet, 1974, ii, 1449. 1. Biro, V., Goldenberg, D. M. Chemotherapy, 1971, 16, 29. 2. Buchman, V. M., Vyshinskaya, G. V., Belyanchikova, N. I., Svet-Moldavsky, G. J. Vopros. Oncol. (in the press). 3. Buchman, V. M., Lichinitser, M. R., Svet-Moldavsky, G. J., Mkheidze, D. M. Bull. Exp. Biol. Med. (in the press). 4. Chaube, S., Kreis, W., Uchida, K., Murphy, M. L. Biochem. Pharmac.
1968, 17, 1213. Dollinger, M. R., Burchenal, J. H., Kreis, W., Fox, J. J. ibid. 1967, 16, 689. Evans, J. S., Mengel, G. D. ibid. 1964, 13, 989. Fisher, D. S., Cassidy, E. P., Welsh, A. D. ibid. 1966, 15, 1013. 8. Papac, R. J., Calabresi, P., Hollingworth, J. W., Welch, A. D. Cancer Res. 1965, 25, 1459. 9. Papac, R., Creasey, W. A., Calabresi, P., Welch, A. D. Proc. Am. Ass. 5. 6. 7.
10.
Cancer Res. 1965, 6, 50. Schrecker, A. W., Mead, J. A. R., Urshel, 15, 1443.
EFFECT OF
cdR
M. U. Biochem. Pharmac.
were
and leukaemias. The ascitic form of L1210 leukaemia was induced by weekly transplantation of tumour cells into the peritoneal cavity of DBA/2 mice. The recipients of L1210 leukaemia were adult DBA/2 females and BDF-I hybrid males weighing 22-28 g. All mice were obtained from the Stolbovaya breeding farm of the A.M.S. of the U.S.S.R. We used ’Cytosar’ (lot 217BS, no. tumours
7309, Upjohn, Kalamazoo, Michigan) and 2’-deoxycytidine hydrochloride (lot no. 04015, Reanal, Hungary). The drugs were dissolved in physiological saline solution. In all experiments the treatment was started no earlier than on day 5 after tumour-cell inoculation into mice. Doses and days of inoculation are indicated in the table. The drugs were inoculated intraperitoneally or given orally in 0.2ml volume. CdR was administered orally via a bent metal probe. CdR alone had neither toxic nor anti-tumour effects (see table). The schedule of cytarabine treatment was lethally toxic. At necropsy mice which had received cytarabine alone had no subcutaneous tumours at the site of L1210 cell inoculation; the median spleen and liver weights were much smaller than in healthy non-leukaemic animals (not indicated in the table). CdR inoculation suppressed toxicity of cytarabine, and the combination produced a strong antitumour effect on L1210 leukaemia (see table). In experiment 5 CdR suppressed the development of cytarabine toxicity in 12 of 19 mice; in other experiments all mice escaped toxicity. Thus the CdR/cytarabine combination was effective in the treatment of L1210 leukaemia provided that the cytarabine schedule was lethally toxic. These results and our earlier morphological study of the effect of the CdR/cytarabine combination on haemopoiesis in the bone-marrow from normal mice support the view that the selective effect might be associated with the absence of protection of lymphoid cells. These data should encourage clinical trials of the CdR plus cytarabine combination in the treatment of acute and chronic lymphoid leukaemia, for other forms of neoplasia, and, perhaps, for autoimmune processes as well. VLADIMIR M. BUCHMAN GEORGE J. SVET-MOLDAVSKY MISHA R. LICHINITSER Cancer Research Centre, Moscow 115478, U.S.S.R. DEMURI M. MKHEIDZE
ON EFFICACY OF TOXIC SCHEDULES OF CYTARABINE ADMINISTRATION IN MYELOBLAST AND
LYMPHOBLAST
* 10’ ascites cells of L1210
1966,
not differ from that in mice receiving the antimetabolite alone).2 These data suggested that this combination might result in the selective suppression or eradication of lymphoid
did
L1210
LEUKAEMIA
implanted subcutaneously on day 0 into DBA/2 females in expt.
1 and BDF-I males
in
expts. 5, 6.
1 M.s.r.-median survival-time.
tIn expt. 2 seven mice died of toxicity and form a separate subgroup. From 10 to 13 days they received the drugs In all experiments the drugs were inoculated 4 times/day with an interval of 2 h between injections. § I hese figures do not include 10 mice which have lived for over 50 days.
in
10 times smaller doses.
