Autologous Bone Marrow Transplantation - Blog Science Connections

Proposed International Adult Lymphoma Study 325
only and realizing no significant improvement in length of survival (49-53).
This degree of activity is similar to that of other potentially active single agents
in relapsed large cell lymphoma.
Recent in vitro studies suggest that combining cytarabine with cisplatin
may have a marked synergistic effect. These studies were conducted on
LoVo cells, an established human colon carcinoma line (54). When
combined with other antitumor drugs, cisplatin displayed superadditive
effects with hydroxyurea, bleomycin, cis-retinoic acid, BCNC1 (carmustine),
Adriamycin (doxorubicin), mitomycin C, and an unexpectedly strong
synergistic effect was noted with cytarabine. Although cytarabine displayed
no cytotoxicity on LoVo cells when administered alone, when combined with
cisplatin it induced a several-fold increase in lethality over that attained by
cisplatin alone. The expected-to-observed survival ratios, for a cisplatin
concentration of 5 /ig/ml ranged from 1.3 (cytarabine of 100 fJtg/m\) to 12.9
(cytarabine of 1,000 Ltg/ml), providing a considerably higher performance
index than that observed for cisplatin combined with other drugs tested on
the same cell line. This result is not particularly surprising because it
conforms with previous observations on LI 210 leukemia cells; however, what
is remarkable is that although murine leukemia cells are exquisitely sensitive
to cytarabine, even when it is administered as a single agent, the drug is totally
ineffective against cultured human cells, even at concentrations of 10,000
fig/ml. This supports the conclusion that the marked potentiation observed
for the combination originates from a modification of the nature of the DNA
cross-links induced by cisplatin in the presence of large intracellular
concentrations of cytarabine. Perhaps the simultaneous presence of both
agents induces the formation of multimeric platinum pyrimidine complexes
in a structure similar to the "dimers of dinners" described by Lock et al. (55)
for cisplatin-DNA adducts.
The immediate practical impact of these studies is the rationale they
provide for combining cisplatin and cytarabine in clinical trials. Should the
phenomenon discovered for in vitro cells be shared by in vivo tumors, combining
cisplatin and cytarabine could evolve into an effective form of treatment.
An enhanced therapeutic index is an additional advantage for this
combination because, though the antitumor activity of the paired drugs can
be expected to increase, audiological and renal toxicity, unrelated to DNA
damage, should remain unchanged.
The simultaneous administration of these two agents and dexamethasone
in a pilot study did demonstrate the potential benefit of the combination
for patients with progressive lymphomas with prior resistance to doxorubicin.
Four of fourteen patients have achieved CR, and six other patients achieved
PR. Pathological diagnosis included all types of lymphoma, with a predominance
of diffuse large cell lymphoma (one patient with chronic lymphocytic
leukemia and undifferentiated lymphoma also responded). Renal toxicity
from cisplatin has been reported in up to 36% of patients. Toxicity is dose