Combination and individual antitumor effects of hyperthermia, cisplatin, and selected dithiocarbamates.
The antitumor effects produced by combinations of cisplatin (Pt), substituted dithiocarbamates (dimethyldithiocarbamate [DmDTC] and sodium N-methyl-D-glucamine dithiocarbamate [NMGDTC]) and hyperthermia (H) were measured and compared to those produced by single agents alone in C3H/HeN mice bearing the transplantable radiation-induced fibrosarcoma, RIF-1, in one or both hind feet. The average tumor volumes of control and treatment groups were compared periodically after treatment with H. Combinations of H and Pt completely resolved established foot tumors in 10/13 mice. However, evidence of long-term nephrotoxicity and gastrointestinal (GI) toxicity became evident causing death of these mice within 120 to 122 days after tumor inoculation. Hyperthermia plus DmDTC resolved tumors in heated and non-heated feet in 3/8 mice, thus demonstrating both ipsilateral and contralateral anti-tumor activity. Furthermore, H-Pt-NMGDTC produced complete tumor resolution in 7/13 mice; these mice survived and were tumor-free 180 days post inoculation and autopsies revealed no appreciable nephro- or GI toxicity. In addition, 4/8 mice underwent complete tumor resolution in heated left feet plus dramatic retarding of tumor growth in unheated right feet (ipsilateral and contralateral anti-tumor effects). Five heat-treated left foot tumors resolved in the H-Pt-DmDTC group with one mouse demonstrating resolution of tumor in both feet. Advanced foot tumors were treated with H-DmDTC and H-Pt-DmDTC. Hyperthermia and Pt were administered on day 0 of the experiment and DmDTC on days 0 through 3; dramatic tumor shrinkage continued through day 6 for a total of 75 to 80 percent reduction of tumor volume in both groups. The concurrent administration of DmDTC or NMGDTC with H and Pt prevented or greatly reduced nephrotoxicity and GI toxicity in all experiments without retarding anti-tumor efficacy.
John L. McClellan Memorial Veterans Hospital, Little Rock, AR.
E M
EM
Walker
R F
RF
Schaefer
K J
KJ
Henle
B J
BJ
Schmidt
G R
GR
Gale
D J
DJ
Cannon
M M
MM
Jones
A J
AJ
Moss
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D006979:Hyperthermia, Induced; D051379:Mice; D008809:Mice, Inbred C3H; D013859:Thiocarbamates / Q000008:administration & dosage / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D013859:Thiocarbamates; D002945:Cisplatin